Impaired glucose tolerance without hypertriglyceridemia does not enhance postprandial lipemia.
Postprandial lipemia has been thought to be one of risk factors for coronary heart disease, and enhances in potential patients for atherosclerotic disease. Patients with impaired glucose tolerance (IGT) often show hypertriglyceride, which is caused by enhanced portprandial lipemia. Therefore, postprandial lipemia in patients with IGT and without hypertriglyceridemia has not been cleared. We have examined the levels of plasma triglyceride and chylomicron remnants after a high fat meal load (1250 kcal, 40% fat and 420 mg cholesterol) in 13 normotriglyceridemic subjects with IGT and 10 controls with normal glucose tolerance (NGT). Chylomicron remnants were evaluated as remnant-like particles (RLP) that were not bound to an immunoaffinity gel mixture containing apo A-I and apo B-100 monoclonal antibody. RLP cholesterol levels 4 hours after the fat load were significantly lower in IGT subjects than in NGT subjects. Increase of RLP cholesterol after the fat meal load only significantly correlated with increase of insulin during the first 30 min after a 75 g oral glucose tolerance test, but not fasting lipid, insulinogenic index and HOMA-R (homeostasis model) in all subjects. These results suggest that postprandial response does not enhance in IGT subjects, and may associate with early-phase insulin secretion and without insulin resistance in normotriglyceridemic men with IGT or NGT.


Messaging about very low nicotine cigarettes (VLNCs) to influence policy attitudes, harm perceptions and smoking motivations: a discrete choice experiment.
To reduce smoking and the harms it causes, countries, including the USA, are considering policies to reduce nicotine in combustible tobacco to minimally addictive levels. Effective messages about very low nicotine cigarettes (VLNCs) and this policy are crucial in combating misperceptions threatening the policy's effectiveness. A discrete choice experiment assessed messages about VLNCs. Participants were 590 adults who smoked exclusively, 379 adults who both smoked and used e-cigarettes, 443 adults who formerly smoked and 351 young adults who never smoked (total n=1763). Seven message attributes were varied systematically (source, harm, chemicals, nicotine, satisfaction, addictiveness and quitting efficacy). Outcomes were selection of messages that generated the most positive attitude towards reduced nicotine policy, the greatest perceived harmfulness of VLNCs, and most strongly motivated quitting and initiating behaviour for VLNCs. Information about specific harms and chemicals of VLNCs had the largest effects on selection of messages as eliciting more negative attitudes towards VLNCs policy, increasing perceived VLNC harmfulness, increasing motivation to quit VLNCs and decreasing motivation to try VLNCs. Messages with information about quitting efficacy were selected as more motivating to quit among those who smoke, but also more motivating to try VLNCs among those who do not smoke. Harm and chemical information can be prioritised to ensure VLNCs are not misperceived as less harmful than regular cigarettes. Messages about increased quitting efficacy and reduced addictiveness associated with VLNCs may backfire if presented to those who do not smoke.


Participation in organized sports is positively associated with employment in adults with spinal cord injury.
The aim of this study was to determine the association between participation in organized sports programs and employment in adults with chronic spinal cord injury. This is a cross-sectional study of 149 adults with chronic spinal cord injury. Motor level and completeness of injury were confirmed by physical examination. Information related to demographics, employment, level of education, body mass index, duration of injury, participation in individually planned exercise, and participation in organized sports was obtained using a standardized questionnaire. Multivariable logistic regression analyses were used to assess factors associated with employment. In univariate analyses, employment was associated with younger age (P = 0.001) and a higher level of education (P = 0.01), whereas obesity decreased the likelihood of employment (P = 0.04). Participation in organized sports approached significance (P = 0.06). In the multivariable analysis and after adjusting for age, education, and body mass index, participation in organized sports was significantly associated with employment (odds ratio, 2.4; P = 0.04). Sex, duration of injury, wheelchair use, and participation in individually planned exercise were not significantly associated with employment (P = 0.16-0.94). In the adults with chronic spinal cord injury, participation in organized sports was positively associated with employment. Further studies are necessary to determine the causative nature of this association and how various factors related to sports participation may contribute.


HDAC8 overexpression in mesenchymal stromal cells from JAK2+ myeloproliferative neoplasms: a new therapeutic target?
Histone deacetylases (HDACs) are involved in epigenetic modulation and their aberrant expression has been demonstrated in myeloproliferative neoplasms (MPN). HDAC8 inhibition has been shown to inhibit JAK2/STAT5 signaling in hematopoietic cells from MPN. Nevertheless, the role of HDAC8 expression in bone marrow-mesenchymal stromal cells (BM-MSC) has not been assessed. In the current work we describe that HDAC8 is significantly over-expressed in MSC from in JAK-2 positive MPN compared to those from healthy-donors (HD-MSC). Using a selective HDAC8 inhibitor (PCI34051), we verified that the subsequent decrease in the protein and mRNA expression of HDAC8 is linked with an increased apoptosis of malignant MSC whereas it has no effects on normal MSC. In addition, HDAC8 inhibition in MPN-MSC also decreased their capacity to maintain neoplastic hematopoiesis, by increasing the apoptosis, cell-cycle arrest and colony formation of JAK2+-hematopoietic cells. Mechanistic studies using different MPN cell lines revealed that PCI34051 induced their apoptosis, which is enhanced when were co-cultured with JAK2V617F-MSC, decreased their colony formation and the phosphorylation of STAT3 and STAT5. In summary, we show for the first time that the inhibition of HDAC8 in MSC from JAK2+ MPN patients selectively decreases their hematopoietic-supporting ability, suggesting that HDAC8 may be a potential therapeutic target in this setting by acting not only on hematopoietic cells but also on the malignant microenvironment.


Tjirtamai--'to care for': a nursing education model designed to increase the number of Aboriginal nurses in a rural and remote Queensland community.
In 2009, a nursing education model was locally designed and delivered to support the interest of a group of Aboriginal community members living in a rural and remote town in Queensland, specifically to prepare for entry into further nursing education. Named 'Tjirtamai' by the traditional owners of the area, the program was offered in recognition of the challenges faced by Aboriginal people when they enter nursing education courses and as a way to increase the local number of Aboriginal nurses. This program, while funded by the Government, had unprecedented support and involvement from both the local Aboriginal and wider community. The model offered multiple exit points, assistance with financial and other known challenges for Aboriginal and Torres Strait Islander students, and included contextualised literacy and numeracy. Of the 38 Aboriginal students who enrolled in the course, 26 students completed. Of those students, 18 have since enrolled in a bachelor degree in nursing while another 4 enrolled in a diploma of nursing. This paper provides an overview of the course and its outcomes.


Epidemiology of thyroid microcarcinoma found in autopsy series conducted in areas of different iodine intake.
The prevalence of thyroid microcarcinomas found at autopsies is 100-1000 times higher than in clinical cancer. The epidemiological and histological characteristics of thyroid microcarcinomas in consecutive series of autopsies performed in two areas of different iodine intake were investigated. Iodine deficient (ID) area: n = 222 (M = 109, F = 113), median age: 74-76 years, median iodine excretion (MIE) of nursing home residents from this area: 70 microg/g creatinine. Iodine sufficient (IS) area: n = 221 (M = 132, F = 89), median age: 68 years, MIE: 500 microg/g creatinine. When compared to the IS area, the results obtained in the ID area showed a higher thyroid weight (mean 27.75 g +/- 18.43 g vs. 16.5 g +/- 9.6 g, p < 0.0001) and a larger number of goitrous glands (50/222 vs. 5/221, p < 0.0001). Altogether 21 microcarcinomas were found (4.74%) with no iodine intake- or gender-related difference: ID n = 11 (4.95%), M/F = 8/3; IS n = 10 (4.52%), M/F = 6/4. Microcarcinomas seemed to be more prevalent in the 40-59-year age group. All microcarcinomas were of the papillary type. In conclusion, compared to clinical cancer, thyroid microcarcinomas are characterized by a two-scale higher prevalence, are not related to iodine intake, gender or nodularity, are most exclusively of the papillary type.


Reduced intensity conditioning HLA identical sibling donor allogeneic stem cell transplantation for patients with follicular lymphoma: long-term follow-up from two prospective multicenter trials.
Allogeneic hematopoietic stem cell transplantation is an effective treatment for patients with poor risk lymphoma, at least in part because of the graft-versus-lymphoma effect. Over the past decade, reduced intensity conditioning regimens have been shown to offer results similar to those of conventional high-dose conditioning regimens but with lower toxicity early after transplantation, especially in patients with chemosensitive disease at transplant. The aim of this study was to analyze the long-term outcome of patients with follicular lymphoma who received an HLA identical sibling allogeneic stem cell transplant with a reduced intensity conditioning regimen within prospective trials. The prospective multicenter studies considered included 37 patients with follicular lymphoma who underwent allogeneic stem cell transplantation between 1998 and 2007 with a fludarabine plus melphalan-based reduced intensity conditioning regimen. The median age of the patients was 50 years (range, 34-62 years) and the median follow-up was 52 months (range, 0.6 to 113 months). Most patients (77%) had stage III-IV at diagnosis, and patients had received a median of three lines of therapy before the reduced intensity conditioning allogeneic stem cell transplantation. At the time of transplantation, 14 patients were in complete remission, 16 in partial remission and 7 had refractory or progressive disease after salvage chemotherapy. The 4-year overall survival rates for patients in complete remission, partial remission, or with refractory or progressive disease were 71%, 48% and 29%, respectively (P=0.09), whereas the 4-year cumulative incidences of non-relapse mortality were 26% (95% CI, 11-61), 33% (95% CI, 16-68) and 71% (95% CI, 44-100), respectively. The incidence of relapse for the whole group was only 8% (95% CI, 2-23). We conclude that this strategy of reduced intensity conditioning allogeneic stem cell transplantation may be associated with significant non-relapse mortality in heavily pre-treated patients with follicular lymphoma, but a remarkably low relapse rate. Long-term survival is likely in patients without progressive or refractory disease at the time of transplantation.


Critical factors in assessing exposure to PBDEs via house dust.
Assessment of indoor exposure to polybrominated diphenyl ethers (PBDEs) requires a critical examination of methods that may influence exposure estimates and comparisons between studies. We measured PBDEs in residential dust collected from 20 homes in Boston, MA, to examine 5 key questions: 1) Does the choice of dust exposure metric-e.g., concentration (ng/g) or dust loading (ng/m2)-affect analysis and results? 2) To what degree do dust concentrations change over time? 3) Do dust concentrations vary between rooms? 4) Is the home vacuum bag an acceptable surrogate for researcher-collected dust? 5) Are air and dust concentrations correlated for the same room? We used linear mixed-effects models to analyze the data while accounting for within-home and within-room correlations. We found that PBDE dust concentration and surface loading were highly correlated (r=0.86-0.95, p<0.001). Average dust concentrations did not significantly differ over an 8-month period, possibly because home furnishings changed little over this time. We observed significant differences between rooms in the same home: PBDE concentrations in the main living area were 97% higher than the bedroom for decaBDE (p=0.02) and 72% higher for pentaBDE (p=0.05). Home vacuum bag dust concentrations were significantly lower than researcher-collected dust and not strongly correlated. Air (vapor and particulate phase) and dust concentrations were correlated for pentaBDE (p=0.62, p<0.01), but not for decaBDE (p=0.25). In addition, potential markers of BDE 209 debromination (BDE 202 and the BDE197:BDE201 ratio) were also observed in household dust samples. One vacuum bag sample contained the highest concentrations of BDE 209 (527,000 ng/g) and total PBDEs (544,000 ng/g) that have been reported in house dust.


Multi-organ renal failure in the elderly.
Periodically the question is posed "Why the persistently high mortality in acute renal failure?". By 1986, little progress seemed to have been made in improving outcome and it was stated that once oliguria was resistant to volume replacement and cardiac support, the patient had at best only a 50% chance of surviving. During the period 1960-1985, it can be shown that although outcome was not improving, older and sicker patients were being treated. Reviewing the literature of the past decade, the age and case mix of patients appears stable, but there is no suggestion of improvement in outcome. ARF with sepsis continues to have a mortality of 65 to 80%, and the outcome remains poor in elderly patients with failure of two or more organs. Progress has been slow in Intensive Care Units, and the past 20 years has seen little more than a move away from parenteral towards enteral feeding. Recent advances, however, in ventilatory techniques and the use of supra-physiological doses of glucocorticoids may lead to some improvement in outcome.


Na+, HCO3--cotransporter NBCn1 increases pHi gradients, filopodia, and migration of smooth muscle cells and promotes arterial remodelling.
Arterial remodelling can cause luminal narrowing and obstruct blood flow. We tested the hypothesis that cellular acid-base transport facilitates proliferation and migration of vascular smooth muscle cells (VSMCs) and enhances remodelling of conduit arteries. [Formula: see text]-cotransport via NBCn1 (Slc4a7) mediates net acid extrusion and controls steady-state intracellular pH (pHi) in VSMCs of mouse carotid arteries and primary aortic explants. Carotid arteries undergo hypertrophic inward remodelling in response to partial or complete ligation in vivo, but the increase in media area and thickness and reduction in lumen diameter are attenuated in arteries from NBCn1 knock-out compared with wild-type mice. With [Formula: see text] present, gradients for pHi (∼0.2 units magnitude) exist along the axis of VSMC migration in primary explants from wild-type but not NBCn1 knock-out mice. Knock-out or pharmacological inhibition of NBCn1 also reduces filopodia and lowers initial rates of VSMC migration after scratch-wound infliction. Interventions to reduce H(+)-buffer mobility (omission of [Formula: see text] or inhibition of carbonic anhydrases) re-establish axial pHi gradients, filopodia, and migration rates in explants from NBCn1 knock-out mice. The omission of [Formula: see text] also lowers global pHi and inhibits proliferation in primary explants. Under physiological conditions (i.e. with [Formula: see text] present), NBCn1-mediated [Formula: see text] uptake raises VSMC pHi and promotes filopodia, VSMC migration, and hypertrophic inward remodelling. We propose that axial pHi gradients enhance VSMC migration whereas global acidification inhibits VSMC proliferation and media hypertrophy after carotid artery ligation. These findings support a key role of acid-base transport, particularly via NBCn1, for development of occlusive artery disease.


The Validity of the Comparative Interrupted Time Series Design for Evaluating the Effect of School-Level Interventions.
In this article, we examine whether a well-executed comparative interrupted time series (CITS) design can produce valid inferences about the effectiveness of a school-level intervention. This article also explores the trade-off between bias reduction and precision loss across different methods of selecting comparison groups for the CITS design and assesses whether choosing matched comparison schools based only on preintervention test scores is sufficient to produce internally valid impact estimates. We conduct a validation study of the CITS design based on the federal Reading First program as implemented in one state using results from a regression discontinuity design as a causal benchmark. Our results contribute to the growing base of evidence regarding the validity of nonexperimental designs. We demonstrate that the CITS design can, in our example, produce internally valid estimates of program impacts when multiple years of preintervention outcome data (test scores in the present case) are available and when a set of reasonable criteria are used to select comparison organizations (schools in the present case).


Understanding and Navigating the Repercussions of the Politically Polarized Climate in Mental Health.
The world is experiencing a moment of political polarization between liberal and conservative ideas, which has aggravated since the arrival of the Covid-19. Many countries (Brazil included) have been experiencing the generalized occurrence of people fighting over politics, in contexts including family, workplace, friendships, and romantic relationships. Over the past 2 years, it has been possible to observe an unexpected and overwhelming effect of the political climate on psychotherapy patients, some of whom have started to actively look for therapists who share their convictions. Brazil is experiencing a moment of severe sanitary, economic, social, and political crisis, which is directly affecting our patients. Nevertheless, the impact of the political climate on our population has not been systematically investigated. However, as the political environment is an inherent part of the social component of the psychosocial model, it is important that mental health professionals be prepared to have this conversation with their patients. This highlights the need to address these difficulties in supervision, rounds, and clinical discussions.


Weight is not an accurate criterion for adult cardiac transplant size matching.
Owing to the limited availability of donor hearts, standard donor criteria for heart size matching need to be reexamined. The current practice at most centers is to match the donor's body weight to within +/- 20% of the recipient's. Our hypothesis was that minimal differences exist in heart sizes of the adult donor population, and therefore, the donor pool could be expanded for any given patient. M-mode echocardiographic measurements of left and right ventricular internal dimensions, left ventricular mass, and percent fractional shortening were reviewed in 235 normal adult subjects (101 men, 134 women). Low correlation coefficients and a high degree of variance were consistently observed between cardiac parameters and body size. There were no significant differences in left ventricular internal dimension when women weighing 40 to 109 kg were compared with men statistically different among men weighing 50 to 99 kg. No difference was noted in right ventricular size among men and women. Echocardiography is a simple and accurate technique to assess cardiac dimensions. Body weight does not correlate well with adult cardiac size and should not be used as an exclusion criterion for a donor heart.


Safety and efficacy of ureteroscopy and stone fragmentation for pediatric renal stones: a systematic review.
Flexible ureteroscopy (FURS) is now commonly used for the treatment of paediatric renal stones. We conducted a systematic review of literature looking at the outcomes of flexible ureteroscopy and laser lithotripsy (FURSL) for paediatric stone disease. A systematic review was conducted in a Cochrane style and in accordance PRISMA checklist using MEDLINE, CINAHL, EMBASE, Scopus, and Cochrane library for all English language articles in patients ≤18 years from 1990-2018 who underwent FURSL. A total of 11 studies reported on 431 patients, with a mean age of 8.5 years (range, 0.25-17 years). The mean stone size was 13 mm (range, 1.5-30 mm). The overall stone free rate (SFR) was 87% (58-100%) with a mean complication rate of 12.6% (n=55) (range, 0-31.3%) and 76% needing a post-operative ureteric stent insertion. Of the complications, Clavien I/II complications included fever and urinary tract infection (UTI) (n=19), haematuria (n=7), stent discomfort/stent symptoms/post-operative pain (n=8), voiding disturbance (n=2) and post-operative nausea and vomiting (n=1). Clavien III complications included ureteral injury which included perforation (n=6), urinoma (n=1), and acute urinary retention secondary to stone fragmentation (n=1). Clavien IV complications were urinoma (n=2) and no Clavien V complications were noted. Our review suggests that ureteroscopy and laser stone fragmentation for paediatric population is a safe and effective treatment with good SFR and a low risk of complications.


Mechanisms and implications of transcription blockage by guanine-rich DNA sequences.
Various DNA sequences that interfere with transcription due to their unusual structural properties have been implicated in the regulation of gene expression and with genomic instability. An important example is sequences containing G-rich homopurine-homopyrimidine stretches, for which unusual transcriptional behavior is implicated in regulation of immunogenesis and in other processes such as genomic translocations and telomere function. To elucidate the mechanism of the effect of these sequences on transcription we have studied T7 RNA polymerase transcription of G-rich sequences in vitro. We have shown that these sequences produce significant transcription blockage in an orientation-, length- and supercoiling-dependent manner. Based upon the effects of various sequence modifications, solution conditions, and ribonucleotide substitutions, we conclude that transcription blockage is due to formation of unusually stable RNA/DNA hybrids, which could be further exacerbated by triplex formation. These structures are likely responsible for transcription-dependent replication blockage by G-rich sequences in vivo.


Genetic susceptibility model of Parkinson's disease resulting from exposure of DJ-1 deficient mice to MPTP: evaluation of neuroprotection by Ubisol-Q10.
Parkinson's disease arises from a combination of environmental and genetic risk factors. At present neither the curative nor preventative therapies are available; hence, there is an urgent need to develop reliable animal models to facilitate their development. Water soluble nanomiceller formulation of CoQ10 (Ubisol-Q10) has shown neuroprotection against neurotoxin on human neuronal cells. We have combined the genetic deficiency of DJ-1/PARK7 mice with MPTP exposure and develop a genetic susceptibility model of PD and evaluated the neuroprotective efficacy of (Ubisol-Q10). Transgenic mice with DJ-1 deficiency (DJ-1/PARK7) were given either water or Ubisol-Q10 prophylactically at a dose of 6 mg/kg/day added directly to a drinking water for one month followed challenged with MPTP injections while keeping the same drinking water regiments. Four weeks after the last injection we evaluated neuroprotective efficacy of Ubisol-Q10 in DJ-1/MPTP model of PD using histochemical and behavioral readouts. We confirmed genetic susceptibility to MPTP and showed that prophylactic oral treatment with Ubisol-Q10 significantly offset the neurotoxicity and ameliorated motor dysfunction, otherwise correlated with the MPTP injury. Ubisol-Q10 protects against MPTP-induced neurodegeneration and motor dysfunction in DJ-1 deficient mice. Ubisol-Q10 might be a treatment prospect for people genetically predisposed to PD as well as with sporadic PD.


Liquidity, Technological Opportunities, and the Stage Distribution of Venture Capital Investments.
This paper explores the determinants of the stage distribution of European venture capital investments from 1990 to 2011. Consistent with liquidity risk theory, we find that the likelihood of investing in earlier stages increases relative to all private equity investments during liquidity crisis years. While liquidity is the main driver of acquisition investments and, to some extent, of expansion financings, technological opportunities are overall the main driver of early and late stage venture capital investments. In contrast to the dotcom crash, the recent financial crisis negatively affected the relative likelihood of expansion investments, but not of early and late stage investments.


Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants.
Patent ductus arteriosus (PDA) with significant left to right shunt in preterm infants increases morbidity and mortality. Early closure of the ductus arteriosus may be achieved pharmacologically using cyclooxygenase inhibitors, or by surgery. The efficacy of both treatment modalities is well established. However, the preferred initial treatment of a symptomatic PDA in a preterm infant, surgical ligation or trial of indomethacin, has not been well established. To compare the effect of surgical ligation of PDA versus medical treatment with cyclooxygenase inhibitors (using indomethacin, ibuprofen, or mefenamic acid), each used as the initial treatment, on neonatal mortality in preterm infants with a symptomatic PDA. The standard search strategy of the Cochrane Neonatal Review Group was used. This included search of electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2002), MEDLINE (1966 - December 2002), CINAHL (1982 - December 2002), EMBASE (1980 - December 2002); and hand search of abstracts of Pediatric Academic Societies annual meetings published in Pediatric Research (1990 - April 2002). No language restrictions were applied. All trials 1) using randomized or quasi-randomized patient allocation, 2) in preterm infants < 37 weeks gestational age or low-birth-weight infants (< 2500 grams) with symptomatic PDA in the neonatal period (< 28 days) and 3) comparing surgical ligation with medical treatment with cyclooxygenase inhibitors, each used as the initial treatment for closure of PDA. Assessment of methodological quality and extraction of data for included trials was undertaken independently by the authors. RevMan 4.1 was used for analysis of the data. Only one study, trial B in the report of Gersony 1983, was found eligible. The trial compared the effect of surgical ligation of PDA versus medical treatment with indomethacin, each used as the primary treatment. No trials comparing surgery to other cyclooxygenase inhibitors (ibuprofen, mefenamic acid) were found. Trial B of Gersony 1983 enrolled 154 infants. The study found no statistically significant difference between surgical closure and indomethacin treatment in mortality during hospital stay, chronic lung disease, other bleeding, necrotizing enterocolitis, sepsis, creatinine level, or intraventricular hemorrhage. There was a statistically significant increase in the surgical group in incidence of pneumothorax [RR 2.68 (95% CI 1.45, 4.93); RD 0.25 (95% CI 0.11, 0.38); NNH 4 (95% CI 3, 9)] and retinopathy of prematurity grade III and IV [RR 3.80 (95% CI 1.12, 12.93); RD 0.11 (95% CI 0.02, 0.20), NNH 9 (95% CI 5, 50] compared to the indomethacin group. There was as expected a statistically significant decrease in failure of ductal closure rate in the surgical group as compared to the indomethacin group: [RR 0.04 (95% CI 0.01, 0.27); RD -0.32 (95% CI -0.43, -0.21), NNT 3 (95% CI 2, 4)]. The data regarding net benefit/harm are insufficient to make a conclusion as to whether surgical ligation or medical treatment with indomethacin is preferred as initial treatment for symptomatic PDA in preterm infants.


Accuracy of unenhanced computerized tomography interpretation by urologists in patients with acute flank pain.
The aim was to compare the findings of non-contrast computerized tomography (NCCT) evaluated by urology specialists with the findings of experienced radiologists, who are accepted as a standard reference for patients who present with acute flank pain. Five hundred patients evaluated with NCCT were included in the study. The NCCT images of these patients were evaluated by both radiologists and urology specialists in terms of the presence of calculus, size of calculus, the location of calculus, the presence of hydronephrosis, and pathologies other than calculus, and the results were compared. The evaluations of urology specialists and standard reference radiology specialists are consistent with each other in terms of the presence of calculus (kappa [κ]: 0.904), categorical stone size (κ: 0.81), the location of calculus (κ: 0.88), and hydronephrosis (κ: 0.94). However, the evaluations of urology specialists in detecting pathologies other than calculus, which may cause acute flank pain or accompany renal colic, were found to be inadequate (κ: 0.37). The false-negative rate of detecting pathologies outside of the urinary system by the urology specialists is calculated as 0.86. Although the urology specialists can evaluate the findings related to calculus sufficiently with NCCT, they may not discover pathologies outside of the urinary system.


Structure and stability of beta-pleated sheets.
Beside alpha-helices, beta-sheets are the most common secondary structure elements of proteins. In this article, the question of structure and stability of parallel and antiparallel sheets of various lengths is addressed. All data obtained are compared to a selected set of protein structures. In antiparallel beta-sheets, one of the two possible H-bonded structures (containing 14 atoms in the H-bonded pseudoring) is energetically more favored and also more abundant in proteins than the other one (with 10 atoms involved in the pseudoring). Parallel beta-sheets and their subunits are energetically less stable and indeed found to occur more rarely in proteins. Antiparallel hairpins are disfavored compared to beta-sheets formed by sequentially separated strands. Agreement between theory and experimental data indicates that characterization of structural building blocks at an appropriately accurate level of theory is a useful tool to get insight into fundamentals of protein structure.


Vaginal delivery or cesarean section at term breech delivery--chance or risk?
The aim of the study was to examine maternal age, parity, and estimated neonatal birth weight (BW) depending on the mode of a full-term breech presentation (BP) birth delivery and neonatal outcomes. One hundred and forty-six singleton term breech presentation pregnancies were included in a retrospective study conducted at the Department of Gynecology/Obstetrics, Clinical Center of Serbia in Belgrade in 2013. Statistical analysis: Student's-t test, χ(2) likelihood ratio, and the Fisher's exact test. The level of statistical significance was set at p <0.05. An ECS was the most common mode of delivery in (81.2%) nulliparous older than 35 years and most of the neonates (66.67%) with an estimated birth weight (BW) above 3500 grams were delivered by elective cesarean section (ECS). Perinatal asphyxia remained increased in the successful vaginal delivery (SVD) group (23.8%) compared with the urgent CS (UCS) group (13.3%) (p = 0.035). Birth asphyxia was the most common in neonates were delivered by SVD (23.8%). There were no cases of perinatal deaths. ECS remained the recommended mode of breech term delivery in nulliparous women older than 35 years, as well as in neonates with an estimated BW above 3500 grams.


Only free bile acid drives ileal absorption of taurocholate.
We compared the intestinal absorption of monomeric taurocholate bound to albumin with the absorption of the free form. In the presence of albumin the apparent uptake coefficient is about three times greater than that in its absence. This result resembles the one reported previously for the liver. In the gut, however, this phenomenon is attributable to the diffusive resistance of an unstirred intervillous fluid layer, whereas in the liver this explanation has been excluded. We conclude that only free taurocholate engages the bile acid transport system in ileal mucosa, whereas in the liver bile acid uptake is driven by albumin-taurocholate complexes, as well as by free taurocholate.


The ethics of teamwork.
Some tasks are better accomplished by a successful team effort. Teams do not replace individual achievement; however, some ethical dilemmas cannot be resolved by individuals. Teams and teamwork are defined within the context of a case study. Types of teams, factors that strengthen teams, and circumstances that threaten teams are presented.


Identification of antigen Ag43 in uropathogenic Escherichia coli Dr+ strains and defining its role in the pathogenesis of urinary tract infections.
Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) are amongst the most common bacterial infectious diseases in the developed world. The urovirulence of UPEC is mainly associated with the surface-exposed fimbrial adhesins and adhesins of the autotransporter (AT) family. The best studied of these proteins is antigen Ag43 mediating cell aggregation, adhesion and biofilm development as the causes of chronic UTIs. The E. coli IH11128 Dr(+) (dra (+)) strain of the Dr/Afa(+) family of adhesins possesses two major surface-exposed virulence factors: Dr fimbrial polyadhesin and DraD protein (fimbrial tip subunit or protein component of the adhesive sheath). Here, we identified for the first time, to our knowledge, the agn43 gene encoding Ag43 in the WT clinical isolate of UPEC Dr(+) as a new virulence factor not yet tested. We also found that Dr fimbrial expression, which like Ag43 is under the control of a phase-variable mechanism, did not exclude Ag43 surface presentation. However, the presence of Dr fimbriae supported by other structures on the cell surface caused a physical neutralization of Ag43-mediated autoaggregation during in vitro growth. The fimbrial bundling further increased the distance between the adjacent Ag43(+) cells, thus preventing head-to-tail association between surface-exposed Ag43 subunits and their interactions with the host cells. The investigations showed that Ag43 did not act as a specific adhesin and invasin, conversely to the major virulence factors of E. coli Dr(+), but played significant roles in the viability and metabolic activity of bacterial cells forming biofilm, and in the survival of bacteria within invaded epithelial cells.


[Changes in beta-glucuronidase activity in the blood cells and blood serum of patients with rheumatism in relation to clinical manifestations of the disease].
The authors examined 22 patients with rheumatic fever in whose cells (neutrophils, mononuclear cells, thrombocytes) and in the blood serum they noted the activity of lysosomal enzyme of beta-glucuronidase (BGU) and the concentration of protein in the cells of the peripheral blood. The activity of the enzyme and concentration of protein in neutrophils of mononuclear cells was found to be decreased. Differences in determining the activity of BGU in the blood serum in relation to the clinical manifestations of the disease were also established. A significant rise in the activity of BGU in the blood serum as compared to the norm was observed in patients with a protracted course of rheumatic fever, with the I degree of the process activity, circulatory disorders and complicated cardiac failures. There was a clearly seen direct relationship between the activity of BGU in the blood serum and the level of circulating immune complexes, and an indirect relationship between the mentioned enzyme and alpha 2-globulin. A decrease in the activity of BGU in the cells was caused by degranulation of neutrophils and monocytes induced by immunological factors. A decrease in the level of BGU in the cells of patients with rheumatic fever apparently influences the processes of phagocytosis and aggravates immunological disorders, and, consequently, is connected with the disease pathogenesis. Determination of the BGU activity in the blood serum can be used for detection of the minimum activity of the inflammatory process in a chronic course of rheumatic fever.


Transient noise amplification and gene expression synchronization in a bistable mammalian cell-fate switch.
Progenitor cells within a clonal population show variable proclivity toward lineage commitment and differentiation. This cell-to-cell variability has been attributed to transcriptome-wide gene expression noise generated by fluctuations in the amount of cellular machinery and stochasticity in the biochemical reactions involved in protein synthesis. It therefore remains unclear how a signaling network, in the presence of such noise, can execute unequivocal cell-fate decisions from external cues. Here, we use mathematical modeling and model-guided experiments to reveal functional interplay between instructive signaling and noise in erythropoiesis. We present evidence that positive transcriptional feedback loops in a lineage-specific receptor signaling pathway can generate ligand-induced memory to engender robust, switch-like responses. These same feedback loops can also transiently amplify gene expression noise in the signaling network, suggesting that external cues can actually bias seemingly stochastic decisions during cell-fate specification. Gene expression levels among key effectors in the signaling pathway are uncorrelated in the initial population of progenitor cells but become synchronized after addition of ligand, which activates the transcriptional feedback loops. Finally, we show that this transient noise amplification and gene expression synchronization induced by ligand can directly influence cell survival and differentiation kinetics within the population.


The quest for a general theory of aging and longevity.
Extensive studies of phenomena related to aging have produced many diverse findings, which require a general theoretical framework to be organized into a comprehensive body of knowledge. As demonstrated by the success of evolutionary theories of aging, quite general theoretical considerations can be very useful when applied to research on aging. In this theoretical study, we attempt to gain insight into aging by applying a general theory of systems failure known as reliability theory. Considerations of this theory lead to the following conclusions: (i) Redundancy is a concept of crucial importance for understanding aging, particularly the systemic nature of aging. Systems that are redundant in numbers of irreplaceable elements deteriorate (that is, age) over time, even if they are built of elements that do not themselves age. (ii) An apparent aging rate or expression of aging is higher for systems that have higher levels of redundancy. (iii) Redundancy exhaustion over the life course explains a number of observations about mortality, including mortality convergence at later life (when death rates are becoming relatively similar at advanced ages for different populations of the same species) as well as late-life mortality deceleration, leveling off, and mortality plateaus. (iv) Living organisms apparently contain a high load of initial damage from the early stages of development, and therefore their life span and aging patterns may be sensitive to early-life conditions that determine this initial damage load. Thus, the reliability theory provides a parsimonious explanation for many important aging-related phenomena and suggests a number of interesting testable predictions. We therefore suggest adding the reliability theory to the arsenal of methodological approaches applied to research on aging.


Intercontinental spread of pyrimethamine-resistant malaria.
Here we present molecular evidence demonstrating that malaria parasites bearing high-level pyrimethamine resistance originally arrived in Africa from southeast Asia. The resistance alleles carried by these migrants are now spreading across Africa at an alarming rate, signaling the end of affordable malaria treatment and presenting sub-Saharan Africa with a public health crisis.


Disease Progression in Patients with Autosomal Dominant Retinitis Pigmentosa due to a Mutation in Inosine Monophosphate Dehydrogenase 1 (IMPDH1).
Mutations in the inosine monophosphate dehydrogenase 1 (IMPDH1) gene are a common cause of inherited retinal degeneration (IRD). Due to species- and tissue-dependent expression of IMPDH1, there are no appropriate models of human IMPDH1 disease. Therefore, a limited understanding remains of disease expression and rates of progression for IMPDH1-related IRD. We evaluated semiautomated kinetic and chromatic static perimetry, spectral-domain optical coherence tomography (SD-OCT), and ultra-wide field fundus images with autofluorescence in a cohort of 12 patients (ages 11-58 at first visit). Ten patients had longitudinal data for which rates of progression were estimated. Visual acuities were relatively stable over time and the photoreceptors within the central retina remained intact. Perifoveal photoreceptor loss measured over a period of years coincided with visual fields, which were constricted and progressed over time in all patients. Rod sensitivity showed a similar pattern of defect to that of the kinetic perimetry and the autofluorescence ultra-wide field imaging. Full-field electroretinograms were severely reduced and the dark-adapted rod and mixed responses were extinguished at earlier visits than the light-adapted cone responses. There was variability in disease severity at the first visit, but results show that the peripheral retina is more susceptible to the deleterious consequences of an IMPDH1 mutation. Given the pattern of degeneration and the alternatively spliced isoforms of IMPDH1, potential interventions may consider targeting the periphery early in disease, modulating transcript expression, and/or preserving central vision at late stages of the disease. These results inform clinical prognosis and offer evidence strategies toward therapeutic intervention.


Cardiac remodeling in response to chronic iron deficiency: role of the erythropoietin receptor.
Anemia is a common comorbidity of patients with heart failure, and iron deficiency is known as one of the causes of anemia in heart failure. Recent studies have shown that iron deficiency alone, without overt anemia, is associated with poor outcomes in patients with heart failure. Thus, to minimize the mortality in patients with heart failure, it is important to understand the link between iron deficiency and cardiac function. Chronic untreated iron deficiency results in cardiac remodeling, and we have previously reported that erythropoietin (Epo) and cardiac Epo receptor (EpoR) signaling may be associated with its remodeling. However, the link between EpoR signaling and its remodeling remains to be elucidated. Herein, we investigated the role of EpoR signaling on cardiac remodeling in response to chronic iron deficiency. Wild-type mice and transgene-rescued EpoR-null mutant mice, which express EpoR only in the hematopoietic lineage (EpoR-restricted mice), were fed with either a normal or an iron-restricted diet, and the molecular mechanisms were investigated. Dietary iron restriction gradually induced anemia, Epo secretion, and cardiac hypertrophy in wild-type mice. In contrast, EpoR-restricted mice fed with an iron-restricted diet exhibited anemia, left ventricular dilatation, and cardiac dysfunction compared with wild-type mice. Interestingly, altered cardiac mitochondrial biogenesis was observed in EpoR-restricted mice following iron deficiency. Moreover, cardiac p53 expression was increased in EpoR-restricted mice compared with wild-type mice following iron deficiency. These data indicate that EpoR signaling is associated with cardiac remodeling following chronic iron deficiency.


Urease color test medium U-9 for the detection and identification of "T" mycoplasms in clinical material.
A urease color test fluid medium (U-9) for the detection and identification of T (T-strain) mycoplasmas in clinical material is described which is sensitive and specific for this group of mycoplasmas. The medium was prepared from commercially available components and contained 95% half-strength, tryptic digest broth (pH 5.5), 4% unheated horse serum, 0.05% highest-purity urea, 0.001% sodium phenolsulfonphthalein, and 1,000 units of potassium penicillin G per ml. The final reaction of medium U-9 was pH 6.0. The overall agreement (positive and negative) between urease reactions in U-9 urease color test medium and culture findings in a standard agar primary culture system among 686 clinical specimens was 98.1%. The disagreement consisted of 13 false-positive urease reactions which were recognized visually as false-positive reactions due to other microorganisms. For specimens from the female genitourinary tract, the inclusion of 2.5 mug of amphotericin B (Fungizone) per ml of medium U-9 is recommended for the suppression of growth of Candida species and filamentous fungi.


Effectiveness of a Third Dose of Pfizer-BioNTech and Moderna Vaccines in Preventing COVID-19 Hospitalization Among Immunocompetent and Immunocompromised Adults - United States, August-December 2021.
COVID-19 mRNA vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) provide protection against infection with SARS-CoV-2, the virus that causes COVID-19, and are highly effective against COVID-19-associated hospitalization among eligible persons who receive 2 doses (1,2). However, vaccine effectiveness (VE) among persons with immunocompromising conditions* is lower than that among immunocompetent persons (2), and VE declines after several months among all persons (3). On August 12, 2021, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for a third mRNA vaccine dose as part of a primary series ≥28 days after dose 2 for persons aged ≥12 years with immunocompromising conditions, and, on November 19, 2021, as a booster dose for all adults aged ≥18 years at least 6 months after dose 2, changed to ≥5 months after dose 2 on January 3, 2022 (4,5,6). Among 2,952 adults (including 1,385 COVID-19 case-patients and 1,567 COVID-19-negative controls) hospitalized at 21 U.S. hospitals during August 19-December 15, 2021, effectiveness of mRNA vaccines against COVID-19-associated hospitalization was compared between adults eligible for but who had not received a third vaccine dose (1,251) and vaccine-eligible adults who received a third dose ≥7 days before illness onset (312). Among 1,875 adults without immunocompromising conditions (including 1,065 [57%] unvaccinated, 679 [36%] 2-dose recipients, and 131 [7%] 3-dose [booster] recipients), VE against COVID-19 hospitalization was higher among those who received a booster dose (97%; 95% CI = 95%-99%) compared with that among 2-dose recipients (82%; 95% CI = 77%-86%) (p <0.001). Among 1,077 adults with immunocompromising conditions (including 324 [30%] unvaccinated, 572 [53%] 2-dose recipients, and 181 [17%] 3-dose recipients), VE was higher among those who received a third dose to complete a primary series (88%; 95% CI = 81%-93%) compared with 2-dose recipients (69%; 95% CI = 57%-78%) (p <0.001). Administration of a third COVID-19 mRNA vaccine dose as part of a primary series among immunocompromised adults, or as a booster dose among immunocompetent adults, provides improved protection against COVID-19-associated hospitalization.


The effects of an autologous transplant on patterns of regeneration in rat sciatic nerve.
Autologous transplants are often used in repair of peripheral nerve injury. Quantitative evaluation of the results of such a transplant is obviously desirable. In previous study, we determined numerical and cytologic parameters of the regeneration that followed transection of rat sciatic nerve, but no transplant was used. This work now serves as a basis for evaluating the use of an autologous transplant in the same transection paradigm. Our procedure is to remove 8 mm of sciatic nerve in the thigh. The removed segment is then put into the center of a silicone tube and the proximal and distal stumps of the severed nerve are placed into the ends of the tube. The data show: (1) a high percentage of successful regenerations; (2) a relatively large nerve in the gap; (3) a typical outer perineurium underlying the epineurium; (4) a well-developed fascicular perineurium; and (5) approximately equal numbers of myelinated and unmyelinated axons in the gap and distal stump. If a transplant is not used there are: (1) a greater number of failures of regeneration; (2) a smaller nerve in the gap; (3) a less well-developed fascicular perineurium; (4) unequal numbers of axons in the gap as compared to the distal stump; and (5) no outer perineurium forms. The presence of a typical outer perineurium after a transplant and its absence if a transplant is not used is probably the most striking cytologic difference between the two paradigms. The equal numbers of axons in the gap and distal stump following regeneration after transplantation presumably indicate that all axons in the gap enter the distal stump without branching or ending blindly, a situation that is presumably beneficial and contrasts with the findings when a transplant is not used. Both paradigms show a remarkable increase in the density of blood vessels in the regenerated nerve in the gap between the two stumps. These findings will serve as a basis for further studies on the mechanisms of peripheral nerve regeneration.


Effect of antifungal agents on lipid biosynthesis and membrane integrity in Candida albicans.
Eight antifungal agents were examined for effects on lipid biosynthesis and membrane integrity in Candida albicans. Lipids were labeled in vivo or in vitro with [14C]acetate and analyzed by thin-layer and gas chromatography. Membrane integrity was measured by a recently developed [14C]aminoisobutyric acid radiolabel release assay. The imidazole antifungal agents miconazole, econazole, clotrimazole, and ketoconazole, at concentrations inhibiting ergosterol biosynthesis (0.1 microM), decreased the ratio of unsaturated to saturated fatty acids in vivo but not in vitro. Similarly, naftifine, tolnaftate, and the azasterol A25822B, at concentrations inhibiting ergosterol biosynthesis (10, 100, and 1 microM, respectively), decreased the ratio of unsaturated to saturated fatty acids in vivo only. This suggests that the effect on fatty acids observed with ergosterol biosynthesis inhibitors may be secondary to the effect on ergosterol. With imidazoles, oleic acid antagonized inhibition of cell growth but not inhibition of ergosterol. This suggests that, with the C-14 demethylase inhibitors, decreased unsaturated fatty acids, rather than decreased ergosterol, are responsible for growth inhibition. Cerulenin, previously reported to be a potent inhibitor of both fatty acid and ergosterol biosynthesis, was found in the present study to inhibit the former (at 5 microM) but not the latter (up to 100 microM). Of the antifungal agents tested, econazole and miconazole (at 100 microM) produced complete release of [14C]aminoisobutyric acid, which is consistent with membrane damage.


[Toxic retinopathy in cyclosporin A therapy].
A bone marrow transplantation was performed in a 17-year-old male patient suffering from acute undifferentiated leukemia. The patient received Cyclosporin A--a powerful immunosuppressive agent--to prevent a severe, chronic graft-versus-host disease. While undergoing this therapy the patient suffered a loss of visual acuity in both eyes 17 months after bone marrow transplantation. The substrates of the visual acuity loss were multiple retinal changes. Cotton-wool spots, intraretinal and preretinal hemorrhages were found in both eyes, and a macula edema in the left eye. The possible role of the immuno-suppressive agent Cyclosporin A in the pathogenesis of these changes is discussed.


Currently recommended treatments of childhood constipation are not evidence based: a systematic literature review on the effect of laxative treatment and dietary measures.
Constipation is a common complaint in children and early intervention with oral laxatives may improve complete resolution of functional constipation. However, most treatment guidelines are based on reviews of the literature that do not incorporate a quality assessment of the studies. To investigate and summarise the quantity and quality of the current evidence for the effect of laxatives and dietary measures on functional childhood constipation. The Medline and Embase databases were searched to identify studies evaluating the effect of a medicamentous treatment or dietary intervention on functional constipation. Methodological quality was assessed using a validated list of criteria. Data were statistically pooled, and in case of clinical heterogeneity results were summarised according to a best evidence synthesis. Of the 736 studies found, 28 met the inclusion criteria. In total 10 studies were of high quality. The included studies were clinically and statistically heterogeneous in design. Most laxatives were not compared to placebo. Compared to all other laxatives, polyethylene glycol (PEG) achieved more treatment success (pooled relative risk (RR): 1.47; 95% CI 1.23 to 1.76). Lactulose was less than or equally effective in increasing the defecation frequency compared to all other laxatives investigated. There was no difference in effect on defecation frequency between fibre and placebo (weighted standardised mean difference 0.35 bowel movements per week in favour of fibre, 95% CI -0.04 to 0.74). Insufficient evidence exists supporting that laxative treatment is better than placebo in children with constipation. Compared to all other laxatives, PEG achieved more treatment success, but results on defecation frequency were conflicting. Based on the results of this review, we can give no recommendations to support one laxative over the other for childhood constipation.


Practical strategies to improve treatment of type 2 diabetes.
The purpose of this review was to document the need for, barriers to, and available treatment options for patients with type 2 diabetes, with a focus on modern insulins and delivery systems. Extensive review of the scientific literature was carried out, concentrating on data supporting the need for tight glycemic control, and efficacy and safety data on oral antidiabetes agents, insulins (particularly insulin analog therapies), incretins, and insulin delivery devices. Nurse practitioners and other clinicians need to be aware of the urgent need to help patients optimize glycemic control using therapies that can bring blood glucose levels within the target range throughout the day. Choice of therapy must take into account anticipated hemoglobin A(1c) decrease, tolerability, effect on comorbid conditions, and cost. As diabetes progresses, insulin is the only hypoglycemic agent with unlimited potential to lower blood glucose; earlier initiation of insulin therapy can help many patients achieve glucose targets more rapidly and provide symptomatic relief. Modern insulins and related therapies in conjunction with innovative delivery devices, appropriate counseling, and patient education can help overcome many barriers to insulin therapy. The incidence of type 2 diabetes is increasing at an alarming rate. More aggressive treatment, based on the pathophysiology of the disease, is necessary and should include greater attention to control both fasting and postmeal glucose excursions, as well as earlier introduction of insulin therapy that is both effective and acceptable to patients. The educated use of oral antidiabetes agents, modern insulin analogs, incretin agents, and innovative delivery devices can help many patients achieve blood glucose targets in a scientifically logical manner that takes into account a patient's lifestyle needs.


PySmash: Python package and individual executable program for representative substructure generation and application.
Substructure screening is widely applied to evaluate the molecular potency and ADMET properties of compounds in drug discovery pipelines, and it can also be used to interpret QSAR models for the design of new compounds with desirable physicochemical and biological properties. With the continuous accumulation of more experimental data, data-driven computational systems which can derive representative substructures from large chemical libraries attract more attention. Therefore, the development of an integrated and convenient tool to generate and implement representative substructures is urgently needed. In this study, PySmash, a user-friendly and powerful tool to generate different types of representative substructures, was developed. The current version of PySmash provides both a Python package and an individual executable program, which achieves ease of operation and pipeline integration. Three types of substructure generation algorithms, including circular, path-based and functional group-based algorithms, are provided. Users can conveniently customize their own requirements for substructure size, accuracy and coverage, statistical significance and parallel computation during execution. Besides, PySmash provides the function for external data screening. PySmash, a user-friendly and integrated tool for the automatic generation and implementation of representative substructures, is presented. Three screening examples, including toxicophore derivation, privileged motif detection and the integration of substructures with machine learning (ML) models, are provided to illustrate the utility of PySmash in safety profile evaluation, therapeutic activity exploration and molecular optimization, respectively. Its executable program and Python package are available at https://github.com/kotori-y/pySmash.


Alexithymia Is Associated with Altered Cortical Thickness Networks in the General Population.
Alexithymia is a personality trait characterized by difficulties in identifying and describing emotions and associated with various psychiatric disorders. Neuroimaging studies found evidence for morphological and functional brain alterations in alexithymic subjects. However, the neurobiological mechanisms underlying alexithymia remain incompletely understood. We study the association of alexithymia with cortical correlation networks in a large community-dwelling sample of the Study of Health in Pomerania. Our analysis includes data of n = 2,199 individuals (49.4% females, age = 52.1 ± 13.6 years) which were divided into a low and high alexithymic group by a median split of the Toronto Alexithymia Scale. Cortical correlation networks were constructed based on the mean thicknesses of 68 regions, and differences in centralities were investigated. We found a significantly increased centrality of the right paracentral lobule in the high alexithymia network after correction for multiple testing. Several other regions with motoric and sensory functions showed altered centrality on a nominally significant level. Finding increased centrality of the paracentral lobule, a brain area with sensory as well as motoric features and involvement in bowel and bladder voiding, may contribute to explain the association of alexithymia with functional somatic disorders and chronic pain syndromes.


The perception of the fetus in mothers with liver transplantation. Brief communication.
In this brief note we present the preliminary findings of a study of 16 women who underwent liver transplants before becoming pregnant and giving birth. The aim of the study was to show the similarities and differences between ways women experience the transplanted organ (liver) and the fetus. To explore bodily experiences, a semi-structured ad hoc interview was done on a sample of 16 transplanted women who had completed a pregnancy. The interview was designed to explore the possible similarities between their perception of the transplanted organ (liver) and of the fetus. The main findings that emerge from our study are the following: a) in the post-transplant, pre-pregnancy phase, these women develop a polarized attention on the transplanted organ; b) during pregnancy this attention shifts towards the fetus; c) after childbirth the hyper-attention on the transplanted organ disappears and the subject resumes a normal relationship with her body. Therefore, pregnancy and childbirth are experiences that can normalize relations between a person who has undergone a transplant and their transplanted organ.


Leukodiapedesis, release of PMN leukocyte proteinases and activation of PMNL procollagenase.
Human polymorphonuclear leukocytes mainly protect the body against invading microorganisms. Therefore, cells must migrate to the site of infection, whereby they traverse the endothelial cell layer of the blood vessels, basement membranes and the connective tissue. We investigated the unknown mechanism of penetration of basement membranes by scanning electron microscopy. Our findings indicate a three-step mechanism--adhesion, locally limited proteolytic degradation of matrix components and mechanical loosening of the matrix. Finally, cells locomote in the stroma tissue to the site of infection. These processes are induced by formyl-peptides amongst others. In addition, an increased release of collagenase induced by formyl-peptides was observed. In contrast, incubation with prostaglandin F2 alpha led to significantly higher levels of secreted collagenase, while elastase failed to be detected in the supernatant of stimulated cells. Since it has been shown that collagenase is secreted in a latent form, we have focussed our attention on the activation mechanism of the proenzyme, which was investigated by determination of the N-terminal sequences of intermediate and final, activated forms.


Schedule of taking calcium supplement and the risk of nephrolithiasis.
Variation in the timing of calcium supplement may affect gastrointestinal absorption of both calcium and oxalate differently and may associate with variable risk of calcium oxalate nephrolithiasis. There are few human studies addressing specifically the appropriate time for taking calcium supplement. Therefore, this study was performed to compare calcium bioavailability and the risk of calcium oxalate stone formation for calcium supplement taken with meal vs. taken at bedtime. Thirty-two healthy male navy privates, 22.7 +/- 1.9 years old (mean +/- SD), who had normal renal function (serum creatinine less than 150 umol/L) and no history of renal stone, participated in the study. The subjects were randomly allocated into two groups of 16 each. Group A took 1 g of calcium carbonate with meal, 3 times/day; and group B took 3 g/day of calcium carbonate at bedtime. After taking the regimens for 1 week, followed by 1 month of washout period, crossover between both groups was done. The diet was controlled throughout the study. Twenty-four-hour urine collections for the determination of urinary constituents were obtained at baseline and after taking both regimens of calcium supplement. Activity product for calcium oxalate was determined to assess the risk of calcium oxalate stone formation. Urinary excretions of calcium were significantly elevated above the baseline values when taking calcium supplement both with meal (3.48 +/- 2.13 mmol/day vs. 5.17 +/- 2.61 mmol/day, P < 0.05) and at bedtime (3.09 +/- 1.70 mmol/day vs. 5.08 +/- 2.34 mmol/day, P < 0.05). There was no difference between the two regimens in the urinary calcium excretions. The urinary oxalate was decreased significantly when the subjects took calcium supplement with meal compared with the corresponding baseline value (0.13 +/- 0.05 vs. 0.17 +/- 0.07 mmol/d, P= 0.01). In contrast, there was no alteration in urinary oxalate when calcium supplement was taken at bedtime compared to the baseline values (0.15 +/- 0.05 mmol/day vs. 0.15 +/- 0.06 mmol/day, P= 0.9). Compared with the corresponding baseline values, there was no significant increase in the activity product for calcium oxalate when taking calcium with meal (0.54 +/- 0.25 vs. 0.57 +/- 0.22, P= 0.54), but it was increased significantly when calcium supplement was taken at bedtime (0.47 +/- 0.21 vs. 0.72 +/- 0.27, P < 0.01). Calcium supplement should be taken with meal in order to avoid increasing the risk of calcium oxalate nephrolithiasis.


Soft chemistry of metastable metal chalcogenide nanomaterials.
The metastable nature of metal chalcogenide nanomaterials (MCNs) provides us with fresh perspectives and plentiful grounds in the search of new strategies for physicochemical tuning. In the past decade, numerous efforts have been devoted to synthesizing and modifying diverse emerging MCNs based on their "soft chemistry", that is, gently regulating the composition, structure, phase, and interface while not entirely disrupting the original features. This tutorial review focuses on design principles based on the metastability of MCNs, such as ion mobility and vacancy, thermal and structural instability, chemical reactivity, and phase transition, together with corresponding soft chemical approaches, including ion-exchange, catalytic growth, segregation or coupling, template grafting or transformation, and crystal-phase engineering, and summarizes recent advances in their preparation and modification. Finally, prospects for the future development of soft chemistry-directed synthetic guidelines and metastable metal chalcogenide-derived nanomaterials are proposed and highlighted.


Micronucleus test on Triturus carnifex as a tool for environmental biomonitoring.
The amphibian micronucleus test has been widely used during the last 30 years to test the genotoxic properties of several chemicals and as a tool for ecogenotoxic monitoring. The vast majority of these studies were performed on peripheral blood of urodelan larvae and anuran tadpoles and to a lesser extent adults were also used. In this study, we developed protocols for measuring micronuclei in adult shed skin cells and larval gill cells of the Italian crested newt (Triturus carnifex). Amphibians were collected from ponds in two protected areas in Italy that differed in their radon content. Twenty-three adult newts and 31 larvae were captured from the radon-rich pond, while 20 adults and 27 larvae were taken from the radon-free site. The animals were brought to the laboratory and the micronucleus test was performed on peripheral blood and shed skins taken from the adults and on larval gills. Samples from the radon-rich site showed micronucleus frequencies higher than those from the radon-free site and the difference was statistically significant in gill cells (P < 0.00001). Moreover, the larval gills seem to be more sensitive than the adult tissues. This method represents an easy (and noninvasive in the case of the shed skin) application of the micronucleus assay that can be useful for environmental studies in situ.


Lifecourse socioeconomic status and type 2 diabetes: the role of chronic inflammation in the English Longitudinal Study of Ageing.
We examined the association between lifecourse socioeconomic status (SES) and the risk of type 2 diabetes at older ages, ascertaining the extent to which adult lifestyle factors and systemic inflammation explain this relationship. Data were drawn from the English Longitudinal Study of Ageing (ELSA) which, established in 2002, is a representative cohort study of ≥50-year olds individuals living in England. SES indicators were paternal social class, participants' education, participants' wealth, and a lifecourse socioeconomic index. Inflammatory markers (C-reactive protein and fibrinogen) and lifestyle factors were measured repeatedly; diabetes incidence (new cases) was monitored over 7.5 years of follow-up. Of the 6218 individuals free from diabetes at baseline (44% women, mean aged 66 years), 423 developed diabetes during follow-up. Relative to the most advantaged people, those in the lowest lifecourse SES group experienced more than double the risk of diabetes (hazard ratio 2.59; 95% Confidence Interval (CI) = 1.81-3.71). Lifestyle factors explained 52% (95%CI:30-85) and inflammatory markers 22% (95%CI:13-37) of this gradient. Similar results were apparent with the separate SES indicators. In a general population sample, socioeconomic inequalities in the risk of type 2 diabetes extend to older ages and appear to partially originate from socioeconomic variations in modifiable factors which include lifestyle and inflammation.


Cumulative exposure to remnant cholesterol and the risk of fragility fractures: a longitudinal cohort study.
To investigate the association between cumulative remnant cholesterol (cumRC) and the risk of new-onset fragility fractures. This study included individuals who participated in the 2006, 2008, and 2010 Kailuan health examinations. Baseline characteristics were compared between groups according to cumRC quartiles. The incidence density was calculated, and the log-rank test was used to compare the cumulative incidence. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI), and restricted cubic spline was used to examine the possibly non-linear relation between cumRC and the risk of fragility fractures. Additional analyses were performed with stratification by age (≥ or <65 years). A total of 43,839 individuals were included in this study. During the median follow-up period of 10.97 years, a total of 489 fragility fractures occurred. Multivariable Cox proportional hazards regression model 3 showed that the Q1 and Q4 groups versus the Q2 group were associated with a higher HR of fragility fracture (HR 1.61, 95% CI: 1.23-2.11; HR 1.38, 95% CI: 1.06-1.81), and restricted cubic spline regression analysis showed a non-linear relationship between cumRC level and the risk of fragility fractures (P Overall association < 0.001, P Non-linear association = 0.001). The association was significant in the age group <65 years but not in the age group ≥65 years. The sensitivity analyses were consistent with the main results. Both too high and too low cumRC levels were associated with a greater risk of fragility fractures, and this association was more significant in young and middle-aged people.


Melatonin promotes Bax sequestration to mitochondria reducing cell susceptibility to apoptosis via the lipoxygenase metabolite 5-hydroxyeicosatetraenoic acid.
Extra-neurological functions of melatonin include control of the immune system and modulation of apoptosis. We previously showed that melatonin inhibits the intrinsic apoptotic pathway in leukocytes via stimulation of high affinity MT1/MT2 receptors, thereby promoting re-localization of the anti-apoptotic Bcl-2 protein to mitochondria. Here we show that Bcl-2 sequesters pro-apoptotic Bax into mitochondria in an inactive form after melatonin treatment, thus reducing cell propensity to apoptosis. Bax translocation and the anti-apoptotic effect of melatonin are strictly dependent on the presence of Bcl-2, and on the 5-lipoxygenase (5-LOX) metabolite 5-hydroxyeicosatetraenoic acid (5-HETE), which we have previously shown to be produced as a consequence of melatonin binding to its low affinity target calmodulin. Therefore, the anti-apoptotic effect of melatonin requires the simultaneous, independent interaction with high (MT1/MT2) and low (calmodulin) affinity targets, eliciting two independent signal transduction pathways converging into Bax sequestration and inactivation. MT1/MT2 vs. lipoxygenase pathways are activated by 10(-9) vs. 10(-5)M melatonin, respectively; the anti-apoptotic effect of melatonin is achieved at 10(-5)M, but drops to 10(-9)M upon addition of exogenous 5-HETE, revealing that lipoxygenase activation is the rate-limiting pathway. Therefore, in areas of inflammation with increased 5-HETE levels, physiological nanomolar concentrations of melatonin may suffice to maintain leukocyte viability.


Performance of a redesigned HIV Selectest enzyme-linked immunosorbent assay optimized to minimize vaccine-induced seropositivity in HIV vaccine trial participants.
Vaccine-induced seropositivity (VISP) or seroreactivity (VISR), defined as the reaction of antibodies elicited by HIV vaccines with antigens used in HIV diagnostic immunoassays, can result in reactive assay results for vaccinated but uninfected individuals, with subsequent misclassification of their infection status. The eventual licensure of a vaccine will magnify this issue and calls for the development of mitigating solutions in advance. An immunoassay that discriminates between antibodies elicited by vaccine antigens and those elicited by infection has been developed to address this laboratory testing need. The HIV Selectest is based on consensus and clade-specific HIV peptides that are omitted in many HIV vaccine constructs. The assay was redesigned to enhance performance across worldwide clades and to simplify routine use via a standard kit format. The redesigned assay was evaluated with sera from vaccine trial participants, HIV-infected and uninfected individuals, and healthy controls. The HIV Selectest exhibited specificities of 99.5% with sera from uninfected recipients of 6 different HIV vaccines and 100% with sera from normal donors, while detecting HIV-1 infections, including intercurrent infections, with 95 to 100% sensitivity depending on the clade, with the highest sensitivities for clades A and C. HIV Selectest sensitivity decreased in very early seroconversion specimens, which possibly explains the slightly lower sensitivity observed for asymptomatic blood donors than for clinical HIV cases. Thus, the HIV Selectest provides a new laboratory tool for use in vaccine settings to distinguish the immune response to HIV vaccine antigens from that due to true infection.


Genomic alterations in malignant transformation of Barrett's esophagus.
The incidence of adenocarcinoma in Barrett's esophagus has been increasing rapidly over the past decades. Neoplastic progression is characterized by three well-defined premalignant stages: metaplasia, low-grade dysplasia, and high-grade dysplasia. A genome-wide overview, based on comparative genomic hybridization, was performed, evaluating 30 Barrett's adenocarcinomas and 25 adjacent precursors, i.e., 6 metaplasias, 9 low-grade dysplasias, and 10 high-grade dysplasias. The frequency of losses and gains significantly increased in the subsequent stages of malignant transformation. Losses of 5q21-q23, 9p21, 17p12-13.1, 18q21, and Y were revealed in low-grade dysplasias. This was followed by loss of 7q33-q35 and gains of 7p12-p15, 7q21-q22, and 17q21 in high-grade dysplasias along with high-level amplification (HLA) of 7q21 and 17q21. In the invasive cancers, additional losses of 3p14-p21, 4p, 4q, 8p21, 13q14-q31, 14q24.3-q31, 16q21-q22, and 22q as well as gains of 3q25-q27, 8q23-24.1, 12p11.2-12, 15q22-q24, and 20q11.2-q13.1 were distinguished along with HLAs of 8p12-p22 and 20q11.2-q13.1. Approximately one-third of the alterations in the dysplasias were also found in the adjacent adenocarcinomas, illustrating that multiple clonal lineages can be present in Barrett's esophagus. Novel findings include loss on 7q, gain on 12p, and the observation of several HLAs in high-grade dysplasias. Furthermore, loss of 7q33-q35 was found to represent a significant distinction between low-grade and high-grade dysplasia (P = 0.01), whereas loss of 16q21-q22 and gain of 20q11.2-q13.1 were disclosed to significantly discriminate between high-grade dysplasia and adenocarcinoma (P = 0.02 and P = 0.03, respectively). This inventory of genetic aberrations increases our understanding of malignant transformation in Barrett's esophagus and might provide useful biomarkers for disease progression.


Exploiting Enzyme Plasticity in Virtual Screening: High Efficiency Inhibitors of Glutamate Racemase.
Glutamate racemase is an attractive antimicrobial drug target. Virtual screening using a transition-state conformation of the enzyme resulted in the discovery of several μM competitive inhibitors, dissimilar from current amino acid-like inhibitors, providing novel scaffolds for drug discovery. The most effective of these competitive inhibitors possesses a very high ligand efficiency value of -0.6 kcal/mol/heavy atom, and is effective against three distinct glutamate racemases representing two species of Bacillus. The benefits of employing the transition-state conformation of the receptor in virtual screening are discussed.


[Social costs of diseases: How relevant are they for economic evaluations?]
In the field of the economic evaluation (EE), there is an open debate on the most appropriate perspective to apply. Despite the relevance of the topic, there are hardly any studies that have analyzed the practical consequences of applying the social perspective vs. health care funder. The aim of this study was performed a systematic review of the available evidence to analyze whether the inclusion/exclusion of informal care and/or loss of productivity influence the results and conclusions of economic evaluations. A systematic review of the literature was carried out using PubMed and Econlit databases, to determine the publications that contained EE on Alzheimer, Parkinson and Stroke. Inclusion criteria were: a) full EE of the diseases under study; b) from January 2006-July 2016; and c) in English or Spanish. 6,292 references were identified, of which 245 publications meet the selection criteria and were analyzed. After the full-text analysis, 20 references were selected, of which 27 full EE were obtained (20 corresponding to Alzheimer, 1 to Parkinson and 6 to Stroke). In 20 EE (74.1%) the change of the perspective modifies the results, becoming dominant or increasing the saving of the resources by comparing the alternatives from the social perspective. In the remaining 7, the inclusion of social costs involves an increase in the costs of the intervention evaluated against its control. In a single EE, the conclusions vary when including social costs. The inclusion of social costs can modify the results of EE but their impact on the conclusions is not relevant.


Game over! Wildlife collapse in northern Central African Republic.
The wildlife populations of northern Central African Republic (CAR) have long suffered intense uncontrolled hunting. Socio-political turmoil in northern CAR that started in 2002 resulted in a rebellion in 2006. An aerial sample count was carried out in northern CAR after the ceasefire to assess the impact of this troubled period on wildlife. The survey was flown at the end of the dry season in February-March 2010. It covered a landscape complex of 95,000 km² comprising national parks, hunting reserves and community hunting areas. Comparison with earlier surveys revealed a dramatic decline of wildlife: the numbers of large mammals fell by 94% in 30 years, probably due to poaching, loss of habitat and diseases brought by illegal movements of cattle. Elephant (Loxodonta africana), Reduncinae and topi (Damaliscus lunatus) populations showed the greatest decline (each over 90%). Other species declined by 70-80% during the same period. The future of wildlife in this area is dark without a strong commitment to provide adequate funding and quickly implement of determined field management. Reinforced cooperation with neighbouring Chad and Sudan is required since they are facing similar problems.


Two types of HTLV-1 particles are released from MT-2 cells.
The MT-2 cell line transformed by human T-cell leukemia virus type 1 (HTLV-1) contains one complete provirus and seven defective proviruses. Four defective genomes have an identical structure (LTR-MA-deltaCA-pX-LTR) with an open reading frame that spans from MA to pX, giving rise to a 3.4-kb (24S) RNA transcript encoding a chimeric Gag-pX protein, p28. MT-2 cells release two distinct types of virions. The major "classic" type of particle has a buoyant density of 1.155-1.16 g/cm3 and contains the standard HTLV-I structural proteins and reverse transcriptase (RT). In addition, about 5% of particles are "light," approximately 1.12 g/cm3, and contain p28, RT activity, and the 3.4-kb RNA transcript. RT-PCR and in vitro translation indicate that some of the classic HTLV-1 particles package 3.4-kb RNA as well as full-length 8.5-kb RNA. In addition to matrix features, the p28 protein has a motif resembling a zinc finger at the C-terminal, pX0 region, which may play a role in the assembly of the defective light virions.


A Hybrid Maze Procedure for Long-Standing Persistent Atrial Fibrillation.
Catheter ablation (CA) for long-standing persistent atrial fibrillation (LSPAF) is suboptimal, and open surgical ablation, although more successful, is too invasive to be a first-line therapy. Less invasive hybrid procedures that combine thoracoscopic surgery (TS) with CA have been only marginally more successful for LSPAF than CA alone. Joint hybrid procedures for LSPAF are based on the assumption that AF surgery and CA procedures can be guided by intraoperative mapping. However, intraoperative mapping is not always dependable because of the transient nature of the sustaining reentrant drivers. The best results in patients with LSPAF have been attained with the non-guided, anatomy-based surgical Maze-III and Maze-IV procedures. Likewise, a staged TS/CA hybrid procedure that creates a combination of lesions that adhere to the concept of a Maze pattern, that is, a Hybrid Maze-IV procedure, should be more effective for LSPAF. Initial TS includes all lesions of the Maze-IV procedure except the mitral line, coronary sinus lesion, and one right atrial lesion. Follow-up CA at 3 months includes touching up any incomplete TS lesions, a cavotricuspid isthmus lesion, and a mitral line/coronary sinus lesion in the 10% to 15% of patients with post-TS perimitral flutter. This combination of TS and CA lesions creates a complete Maze-IV procedure. It is possible to create the complete lesion pattern of a Maze-IV procedure with a staged TS/CA hybrid procedure. The success of this Hybrid Maze procedure in patients with LSPAF should be the same as that attained with an open surgical Maze-IV procedure.


Effects of creatine supplementation along with resistance training on urinary formaldehyde and serum enzymes in wrestlers.
Formaldehyde is a cytotoxic agent produced from creatine through a metabolic pathway, and in this regard, it has been claimed that creatine supplementation could be cytotoxic. Even though the cytotoxic effects of creatine supplementation have been widely studied, yet little is known about how resistance training can alter these toxic effects. This study aimed to determine the effects of short-term creatine supplementation plus resistance training on the level of urinary formaldehyde and concentrations of serum enzymes in young male wrestlers. In a double-blind design twenty-one subjects were randomized into creatine supplementation (Cr), creatine supplementation plus resistance training (Cr + T) and placebo plus resistance training (Pl + T) groups. Participants ingested creatine (0.3 g/kg/day) or placebo for 7 days. The training protocol consisted of 3 sessions in one week, each session including three sets of 6-9 repetitions at 80-85% of one-repetition maximum for whole-body exercise. Urine and blood samples were collected at baseline and at the end of the supplementation. Creatine supplementation significantly increased the excretion rate of urinary formaldehyde in the Cr and Cr + T groups by 63.4% and 30.4%, respectively (P<0.05), indicating that resistance training could partially lower this rate by 17.7%. No significant differences were detected in the levels of serum enzymes across time and groups (P>0.05). These findings indicate that resistance training may lower the increase of urinary formaldehyde excretion induced by creatine supplementation, suggesting that creatine consumption could be relatively less toxic when combined with resistance training.


Reverse Genetics of Bat Influenza A Viruses.
New World fruit bats were recently found to harbor two distinct and previously unknown influenza A viruses (IAVs) of the subtypes H17N10 and H18N11. Although viral genome sequences were detected in the liver, intestine, lung, and kidney of infected bats and the complete genome sequences have been isolated from their rectal swab samples, all attempts to isolate an infectious virus from bats in nature have failed. The lack of an infectious bat IAV isolate was overcome by reverse genetic approaches that led to the generation of an infectious virus in vitro. Using such synthetic bat IAVs enabled the identification of their unconventional cell entry via major histocompatibility complex II (MCH-II) molecules and their ability to replicate in mice, ferrets, and bats. Importantly, we also showed that these synthetic recombinant bat IAVs are not able to reassort with conventional IAVs, preventing the acquisition of enhanced transmission properties in non-bat species by reassortment with conventional IAVs. As authentic viruses are key for understanding the molecular biology of bat IAVs, in this chapter, we describe our recently established reverse genetics protocol for generating H17N10 and H18N11 in vitro. This step-by-step protocol starts with cloning of cDNA copies of the viral RNA segments into reverse genetics plasmids, followed by the generation of a highly concentrated stock and finally a method to determine viral titers.


The Radical SAM Heme Synthase AhbD from Methanosarcina barkeri Contains Two Auxiliary [4Fe-4S] Clusters.
In archaea and sulfate-reducing bacteria, heme is synthesized via the siroheme-dependent pathway. The last step of this route is catalyzed by the Radical SAM enzyme AhbD and consists of the conversion of iron-coproporphyrin III into heme. AhbD belongs to the subfamily of Radical SAM enzymes containing a SPASM/Twitch domain carrying either one or two auxiliary iron-sulfur clusters in addition to the characteristic Radical SAM cluster. In previous studies, AhbD was reported to contain one auxiliary [4Fe-4S] cluster. In this study, the amino acid sequence motifs containing conserved cysteine residues in AhbD proteins from different archaea and sulfate-reducing bacteria were reanalyzed. Amino acid sequence alignments and computational structural models of AhbD suggested that a subset of AhbD proteins possesses the full SPASM motif and might contain two auxiliary iron-sulfur clusters (AuxI and AuxII). Therefore, the cluster content of AhbD from Methanosarcina barkeri was studied using enzyme variants lacking individual clusters. The purified enzymes were analyzed using UV/Visible absorption and EPR spectroscopy as well as iron/sulfide determinations showing that AhbD from M. barkeri contains two auxiliary [4Fe-4S] clusters. Heme synthase activity assays suggested that the AuxI cluster might be involved in binding the reaction intermediate and both clusters potentially participate in electron transfer.


Present status and future directions - Guided endodontics.
Luxation injuries and other stimuli may lead to a pulp canal obliteration (PCO). Even though the apposition of tertiary dentine is a sign of a vital pulp, in some cases root canal treatment is indicated in the long term due to apical periodontitis or pulpitis. Depending on the extent of PCO, root canal treatment may be challenging even for experienced and well-equipped endodontic specialists. The 'guided endodontics' (GE) technique was introduced 6 years ago as an alternative to conventional access cavity preparation for teeth with PCO and apical pathosis or irreversible pulpitis. Using three-dimensional radiological imaging such as cone-beam computed tomography and a digital surface scan, an optimal access to the orifice of the calcified root canal can be planned virtually with appropriate software. GE is implemented either with the help of templates analogous to guided implantology (= static navigation) or by means of dynamic navigation based on a camera-marker system. GE has emerged as a field of research in the last 6 years with very promising laboratory-based results regarding the accuracy of guided endodontic access cavities for both static and dynamic navigation. Clinical implementation seems to provide favourable results, but the evidence is mainly based on numerous case reports and a few case series. This narrative review aims to provide an update on the present status of GE and to identify relevant research areas that could contribute to further improvements of this technique.


Characterization of Low Back Pain in Pilots and Maintenance Technicians on a Commercial Airline.
Lower back pain (LBP) is the most common complaint worldwide and the leading cause of disability in the workplace. In Colombia there are no epidemiological data on low back pain in aviation. This study aimed to characterize lower back pain in pilots and maintenance technicians in a Colombian commercial airline. Information was collected from the total population in a Colombian commercial airline in Bogota during the period from 2011 to 2013 using a voluntary survey which requested demographics, occupational (LEST survey) factors, back pain, and chronic pain (chronic pain grade scale). The prevalence rate of LBP in pilot respondents was 71% and the factors associated previously have belonged to the military forces: occupational exposure to physical load and work time. Chronic low back pain was at a prevalence of 49%. The prevalence of LBP in maintenance technicians was 65%. Associated factors were again similar to military forces and included mental workload. Chronic pain had a prevalence of 65%. Factors associated with chronic low back pain were the technicians' time in office and physical load. The prevalence of lower back pain in pilots is similar to that presented in the airline world population. In the case of maintenance technicians, the prevalence was higher than those found in other similar groups, but very similar to prevalences presented in different business industries, including the transport sector. Fajardo Rodriguez HA, Ortiz Mayorga VA. Characterization of low back pain in pilots and maintenance technicians on a commercial airline. Aerosp Med Hum Perform. 2016; 87(9):795-799.


[Fatalities in the course of hospitalization in a psychiatric hospital (paragraph 63 StGb)].
On the average, every tenth proband dies during his compulsory referral to a psychiatric hospital decreed by a court of law. The mortality rate among sentenced persons is not only much higher than that of inmates of a normal prison, but is also much higher than among patients of psychiatric hospitals not compulsorily referred by court. Those who died during hospitalisation, were fully exculpated more often than those who survived at the end of their term; furthermore, they had served their sentences on the average for a longer time than the survivors. The combination of mental disease, legal culpability and imprisonment exercises a particularly dramatic effect on the suicide rate.


Moringa oleifera extract enhances sexual performance in stressed rats.
Aphrodisiacs are required to improve male sexual function under stressful conditions. Due to the effects of oxidative stress and dopamine on male sexual function, we hypothesized that Moringa oleifera leaves might improve male sexual dysfunction induced by stress. Therefore, the effects on various factors playing important roles in male sexual behavior, such as antioxidant effects, the suppression of monoamine and phosphodiesterase type 5 (PDE-5) activities, serum testosterone and corticosterone levels, and histomorphological changes in the testes, of a hydroethanolic extract of M. oleifera leaves were investigated. Various doses of extract including 10, 50, and 250 mg/kg body weight (BW) were given orally to male Wistar rats before exposure to 12 h-immobilization stress for 7 d. The results demonstrated that the extract showed both antioxidant and monoamine oxidase type B (MAO-B) suppression activities. At 7 d of treatment, the low dose of extract improved sexual performance in stress-exposed rats by decreasing intromission latency and increasing intromission frequency. It also suppressed PDE-5 activity, decreased serum corticosterone level, but increased serum testosterone, numbers of interstitial cells of Leydig and spermatozoa. The increased numbers of interstitial cells of Leydig and spermatozoa might have been due to the antioxidant effect of the extract. The increased sexual performance during the intromission phase might have been due to the suppression of MAO-B and PDE-5 activities and increased testosterone. Therefore, M. oleifera is a potential aphrodisiac, but further research concerning the precise underlying mechanisms is still needed.


Electric quadrupole moment of graphene and its effect on intermolecular interactions.
Carbon atoms in aromatic compounds exhibit a permanent electric quadrupole moment due to the aromatic π electron distribution. In the case of small aromatic hydrocarbons, this quadrupole contributes significantly to their intermolecular interactions, but when the honeycomb lattice is expanded to infinity, the quadrupolar field sums to zero and its significance vanishes. Therefore, electrostatic interactions with graphene are often omitted in force field molecular modeling. However, for a finite sheet, the electrostatic field decays only slowly with increasing size and is always non-negligible near edges. In addition, in a corrugated graphene sheet, the electrostatic field near the surface does not vanish completely and remains sizeable. In the present study, we investigated the magnitude of the graphene quadrupolar field as a function of model size and graphene corrugation, and estimated the error resulting from its neglect in molecular dynamics simulations. Exfoliation energies in benzene and hexafluorobenzene were calculated using the potential of mean force method with and without explicit quadrupoles. The effect on exfoliation energies was found to be quite small. However, the quadrupole moment may be important for graphene sheet association (aggregation) as it affects barrier heights, and consequently kinetics of association. Our results indicate that quadrupolar interactions may need to be considered in molecular modeling when graphene is corrugated or bent.


Two types of somatostatin receptors differentiated by cyclic somatostatin analogs.
Somatostatin receptors in rat brain, pituitary, and pancreas were labeled with two radioiodinated analogs of somatostatins 14 and 28. Two cyclic analogs of somatostatin, SMS201-995 and cyclo(Ala-Cys-Phe-D-Trp-Lys-Thr-Cys), showed biphasic displacement of binding to somatostatin receptors by these radioligands. In contrast, all other somatostatin analogs, including somatostatin-14, competed for the receptor sites with monophasic displacement of radioligand receptor binding. Thus two types of somatostatin receptors were identified. It was found that the pituitary and pancreas have predominantly one type of somatostatin receptor whereas the brain has both, and that different regions of the brain have various proportions of the two types. These findings suggest methods to characterize other types of somatostatin receptors subserving somatostatin's diverse physiological functions, including a potential role in cognitive function and extrapyramidal motor system control.


Lentiviral vector integration profiles differ in rodent postmitotic tissues.
Lentiviral vectors with self-inactivating (SIN) long terminal repeats (LTRs) are promising for safe and sustained transgene expression in dividing as well as quiescent cells. As genome organization and transcription substantially differs between actively dividing and postmitotic cells in vivo, we hypothesized that genomic vector integration preferences might be distinct between these biological states. We performed integration site (IS) analyses on mouse dividing cells (fibroblasts and hematopoietic progenitor cells (HPCs)) transduced ex vivo and postmitotic cells (eye and brain) transduced in vivo. As expected, integration in dividing cells occurred preferably into gene coding regions. In contrast, postmitotic cells showed a close to random frequency of integration into genes and gene spare long interspersed nuclear elements (LINE). Our studies on the potential mechanisms responsible for the detected differences of lentiviral integration suggest that the lowered expression level of Psip1 reduce the integration frequency in vivo into gene coding regions in postmitotic cells. The motif TGGAA might represent one of the factors for preferred lentiviral integration into mouse and rat Satellite DNA. These observations are highly relevant for the correct assessment of preclinical biosafety studies, indicating that lentiviral vectors are well suited for safe and effective clinical gene transfer into postmitotic tissues.


The immunolocalization and possible role of c-Met (MET, hepatic growth factor receptor) in the developing human fetal mandibular condyle.
The c-Met system is involved in skeletogenesis and is expressed in the cartilage of growth plates. However, the localization and role of c-Met during endochondral ossification of developing mandibular condyles or during intramembranous ossification has not yet been elucidated. In this study, c-Met was examined immunohistochemically in the mandibles of human fetuses during weeks 9 and 16 of pregnancy. c-Met was immunolocalised in the whole area of the developing mandible, although to different extents. In the intramembranous bone, mesenchymal cells showed a weak immunopositivity. Osteoprogenitor cells demonstrated a moderate immunopositivity for c-Met, while osteoblasts and osteocytes showed a very strong immunolabelling of c-Met. In the developing mandibular condyles, c-Met immunopositivity increased gradually throughout the proliferative layer towards the pre-hypertrophic cell layer, whereas the cells of the hypertrophic layer were weakly immunopositive. These findings have demonstrated, for the first time, the prominent immunolocalization of c-Met in osteogenic and chondrogenic tissues of developing human mandibles, which indicates possible functions for this receptor during mandibular development.