Investigation of genotoxicity risk and DNA repair capacity in breast cancer patients using anastrozole.
Breast cancer is the most common cancer in women worldwide and the incidence increases in postmenopausal women. Anastrozole is a non-steroidal (type II), third-generation aromatase inhibitor (AI) that is used in the treatment of postmenopausal estrogen-related breast cancer. Several studies have been conducted to assess the efficacy, safety, and superiority of AIs to tamoxifen; however, a literature search did not reveal a study that investigated the genotoxic potential of AIs. The aim of this study was to investigate the possible DNA damage risk profile and individual DNA repair capacity of patients using anastrozole with the modified alkaline comet assay in order to contribute to public health and health economics. Women diagnosed with breast cancer after menopause comprised the study group. Six patients who had taken anastrozole for at least 6 months were retrospectively enrolled, and 12 patients who had not yet received treatment were prospectively enrolled as a control group. Peripheral blood lymphocytes were used to measure oxidized DNA damage using formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (endo III) in a modified comet assay. Individual DNA repair capacity was evaluated with the comet assay after a hydrogen peroxide (H2O2) challenge to examine the difference in DNA damage susceptibility. Analysis of DNA damage, oxidative base damage, susceptibility to DNA damage, and repair capacity revealed no significant difference between the control group and the patients taking anastrozole (p>0.05). Susceptibility to H2O2 damage was observed to increase with age (p<0.05). According to the results obtained in this study, anastrozole did not contribute to oxidative DNA damage. An H2O2 challenge with the comet assay is useful to evaluate circumstances of increased vulnerability to damage, such as aging and cancer.


Timing of Blood Sample Processing Affects the Transcriptomic and Epigenomic Profiles in CD4+ T-cells of Atopic Subjects.
Optimal pre-analytical conditions for blood sample processing and isolation of selected cell populations for subsequent transcriptomic and epigenomic studies are required to obtain robust and reproducible results. This pilot study was conducted to investigate the potential effects of timing of CD4+ T-cell processing from peripheral blood of atopic and non-atopic adults on their transcriptomic and epigenetic profiles. Two heparinized blood samples were drawn from each of three atopic and three healthy individuals. For each individual, CD4+ T-cells were isolated from the first blood sample within 2 h (immediate) or from the second blood sample after 24 h storage (delayed). RNA sequencing (RNA-Seq) and histone H3K27 acetylation chromatin immunoprecipitation sequencing (ChIP-Seq) analyses were performed. A multiplicity of genes was shown to be differentially expressed in immediately processed CD4+ T-cells from atopic versus healthy subjects. These differences disappeared when comparing delayed processed cells due to a drastic change in expression levels of atopy-related genes in delayed processed CD4+ T-cells from atopic donors. This finding was further validated on the epigenomic level by examining H3K27 acetylation profiles. In contrast, transcriptomic and epigenomic profiles of blood CD4+ T-cells of healthy donors remained rather unaffected. Taken together, for successful transcriptomics and epigenomics studies, detailed standard operation procedures developed on the basis of samples from both healthy and disease conditions are implicitly recommended.


Healing rates for challenging rotator cuff tears utilizing an acellular human dermal reinforcement graft.
This study presents a retrospective case series of the clinical and structural outcomes (1.5 T MRI) of arthroscopic rotator cuff repair with acellular human dermal graft reinforcement performed by a single surgeon in patients with large, massive, and previously repaired rotator cuff tears. Fourteen patients with mean anterior to posterior tear size 3.87 ± 0.99 cm (median 4 cm, range 2.5-6 cm) were enrolled in the study and were evaluated for structural integrity using a high-field (1.5 T) MRI at an average of 16.8 months after surgery. The Constant-Murley scores, the Flexilevel Scale of Shoulder Function (Flex SF), scapular plane abduction, and strength were analyzed. MRI results showed that the rotator cuff repair was intact in 85.7% (12/14) of the patients studied. Two patients had a Sugaya Type IV recurrent tear (2 of 14; 14.3%), which were both less than 1 cm. The Constant score increased from a preoperative mean of 49.72 (range 13-74) to a postoperative mean of 81.07 (range 45-92) (P value = 0.009). Flexilevel Scale of Shoulder Function (Flex SF) Score normalized to a 100-point scale improved from a preoperative mean of 53.69 to a postoperative mean of 79.71 (P value = 0.003). The Pain Score improved from a preoperative mean of 7.73 to a postoperative mean of 13.57 (P value = 0.008). Scapular plane abduction improved from a preoperative mean of 113.64° to a postoperative mean of 166.43° (P value = 0.010). The strength subset score improved from a preoperative mean of 1.73 kg to a postoperative mean of 7.52 kg (P value = 0.006). This study presents a safe and effective technique that may help improve the healing rates of large, massive, and revision rotator cuff tears with the use of an acellular human dermal allograft. This technique demonstrated favorable structural healing rates and statistically improved functional outcomes in the near term. 4. Retrospective case series.


Acute service and disability service providers experiences of joint working to improve health care experiences of people with an intellectual disability compared to non-joint working: A mixed-method systematic review.
Persons with intellectual disabilities require frequent access to acute services. Many also access disability services within the community. Reports and enquiries have highlighted the sub-optimal healthcare provided to this group when accessing healthcare in acute services. Joint working between acute and disability services has been identified as a measure to improve healthcare for this group. A mixed method systematic review was undertaken to explore current evidence of joint working between both service providers. Twelve publications were included, and the data were analysed using thematic analysis. Confusion around responsibility and limited training in acute services prevented joint working from occurring. Information-sharing is pivotal in promoting joint-working, but measures which facilitated it were not always used. Albeit acute services demonstrated a strong commitment to deliver quality care to those with intellectual disabilities. Much of the available research captures the experiences of staff in acute services. There is a paucity of research available exploring experiences of disability service providers.


Sporothrix schenckii Immunization, but Not Infection, Induces Protective Th17 Responses Mediated by Circulating Memory CD4+ T Cells.
Sporotrichosis is a chronic subcutaneous mycosis caused by the Sporothrix schenckii species complex and it is considered an emerging opportunistic infection in countries with tropical and subtropical climates. The host's immune response has a main role in the development of this disease. However, it is unknown the features of the memory cellular immune response that could protect against the infection. Our results show that i.d. immunization in the ears of mice with inactivated S. schenckii conidia (iC) combined with the cholera toxin (CT) induces a cellular immune response mediated by circulating memory CD4+ T cells, which mainly produce interleukin 17 (IL-17). These cells mediate a strong delayed-type hypersensitivity (DTH) reaction. Systemic and local protection against S. schenckii was mediated by circulating CD4+ T cells. In contrast, the infection induces a potent immune response in the skin mediated by CD4+ T cells, which have an effector phenotype that preferentially produce interferon gamma (IFN-γ) and mediate a transitory DTH reaction. Our findings prove the potential value of the CT as a potent skin adjuvant when combined with fungal antigens, and they also have important implications for our better understanding of the differences between the memory immune response induced by the skin immunization and those induced by the infection; this knowledge enhances our understanding of how a protective immune response against a S. schenckii infection is developed.


A biologically inspired neural network controller for ballistic arm movements.
In humans, the implementation of multijoint tasks of the arm implies a highly complex integration of sensory information, sensorimotor transformations and motor planning. Computational models can be profitably used to better understand the mechanisms sub-serving motor control, thus providing useful perspectives and investigating different control hypotheses. To this purpose, the use of Artificial Neural Networks has been proposed to represent and interpret the movement of upper limb. In this paper, a neural network approach to the modelling of the motor control of a human arm during planar ballistic movements is presented. The developed system is composed of three main computational blocks: 1) a parallel distributed learning scheme that aims at simulating the internal inverse model in the trajectory formation process; 2) a pulse generator, which is responsible for the creation of muscular synergies; and 3) a limb model based on two joints (two degrees of freedom) and six muscle-like actuators, that can accommodate for the biomechanical parameters of the arm. The learning paradigm of the neural controller is based on a pure exploration of the working space with no feedback signal. Kinematics provided by the system have been compared with those obtained in literature from experimental data of humans. The model reproduces kinematics of arm movements, with bell-shaped wrist velocity profiles and approximately straight trajectories, and gives rise to the generation of synergies for the execution of movements. The model allows achieving amplitude and direction errors of respectively 0.52 cm and 0.2 radians. Curvature values are similar to those encountered in experimental measures with humans. The neural controller also manages environmental modifications such as the insertion of different force fields acting on the end-effector. The proposed system has been shown to properly simulate the development of internal models and to control the generation and execution of ballistic planar arm movements. Since the neural controller learns to manage movements on the basis of kinematic information and arm characteristics, it could in perspective command a neuroprosthesis instead of a biomechanical model of a human upper limb, and it could thus give rise to novel rehabilitation techniques.


Genetic diversity and population structure of Raffaelea quercus-mongolicae, a fungus associated with oak mortality in South Korea.
Raffaelea quercus-mongolicae is a fungus associated with oak wilt and deemed to cause extensive oak mortality in South Korea. Since the discovery of this fungus on a dead Mongolian oak (Quercus mongolica) in 2004, the mortality continued to spread southwards in South Korea. Despite continued expansion of the disease and associated significant impacts on forest ecosystems, information is lacking about the origin and genetic diversity of R. quercus-mongolicae. Restriction-site-Associated DNA (RAD) sequencing was used to assess genetic diversity and population structure among five populations (provinces) of R. quercus-mongolicae in South Korea. In total, 179 single nucleotide polymorphisms (SNPs) were identified among 2,639 RAD loci across the nuclear genome of the 54 R. quercus-mongolicae isolates (0.0012 SNPs per bp), which displayed an overall low expected heterozygosity and no apparent population structure. The low genetic diversity and no apparent population structure among South Korean populations of this ambrosia beetle-vectored fungus supports the hypothesis that this fungus was introduced to South Korea.


Phase ordering with a global conservation law: Ostwald ripening and coalescence.
Globally conserved phase ordering dynamics is investigated in systems with short range correlations at t=0. A Ginzburg-Landau equation with a global conservation law is employed as the phase field model. The conditions are found under which the sharp-interface limit of this equation is reducible to the area-preserving motion by curvature. Numerical simulations show that, for both critical and off-critical quench, the equal-time pair correlation function exhibits dynamic scaling, and the characteristic coarsening length obeys l(t) approximately t(1/2). For the critical quench, our results are in excellent agreement with earlier results. For off-critical quench (Ostwald ripening) we investigate the dynamics of the size distribution function of the minority phase domains. The simulations show that, at large times, this distribution function has a self-similar form with growth exponent 1/2. The scaled distribution, however, strongly differs from the classical Wagner distribution. We attribute this difference to coalescence of domains. A theory of Ostwald ripening is developed that takes into account binary coalescence events. The theoretical scaled distribution function agrees well with that obtained in the simulations.


Stress testing in nerve compression.
Peripheral nerve compression syndromes most often produce neuropathic changes that are recordable by conventional electrophysiologic testing techniques. Occasionally, a patient exhibits all the appropriate clinical signs, symptoms, and history of a compartment syndrome, such as a carpal tunnel syndrome, but electrophysiologic testing procedures will be normal, thus seeming to identify no neuropathic component to the syndrome. Researchers have reasonably concluded that wrist position or hand activity can have an adverse affect on intracompartmental carpal pressures, with resultant ischemic changes in epineural blood supply and subsequent compromise in nerve conduction parameters during and for a short time after the ischemic event. The stress testing protocol presented here identifies such changes, which would otherwise go undetected or undocumented and which may lead to unsuccessful clinical decisions regarding management. Sample tracings of actual cases are presented to demonstrate actual changes produced by the use of the protocol. This test protocol is used only when conventional testing is normal in the presence of appropriate clinical symptomatology.


Mutation in integrin-linked kinase (ILK(R211A)) and heat-shock protein 70 comprise a broadly cardioprotective complex.
Integrin-linked kinase (ILK) has been proposed as a novel molecular target that has translational potential in diverse cardiac diseases, since its upregulation promotes a broadly cardioprotective phenotype. However, ILK has been implicated as both a cardioprotective and oncogenic target, which imposes therapeutic constraints that are generally relevant to the translational potential of many kinases. To study the cardioprotective properties of the activation-resistant, non-oncogenic, mutation of ILK (ILK(R211A)) against experimental MI in vivo and Doxorubicin induced apoptosis in vitro and it's relationships to stress induced heat shock proteins. The transgenic mouse heart over-expressing a point mutation in the ILK pleckstrin homology (PH) domain (Tg(R211A)) exhibits a highly cardioprotective phenotype based on LAD-ligation-induced MI reduction in vivo, and on protection against doxorubicin (DOX)-induced cardiomyocyte apoptosis when overexpressed in human induced pluripotent stem cell (iPS)-derived cardiomyocytes in vitro. Intriguingly, the degree of cardioprotection seen with the ILK(R211A) mutation exceeded that with the ILK(S343D) mutation. Microarray and immunoprecipitation analyses revealed upregulation of expression levels and specific binding of ILK(WT), ILK(S343D) and ILK(R211A) to both constitutively active heat-shock protein 70 (Hsc70) and inducible Hsp70 in response to MI, and to acute ILK overexpression in iPSC-cardiomyocytes. ILK-mediated cardioprotection was shown to depend upon Hsp70 ATPase activity. These findings indicate that wild type ILK and the non-oncogenic ILK(R211A) mutation comprise a cardioprotective module with Hsp/c70. These results advance a novel target discovery theme in which kinase mutations can be safely engineered to enhance cardioprotective effects.


Long-term stability of skeletal Class III patients treated with splints, Class III elastics, and chincup.
Long-term results from orthopedic management of skeletal Class III malocclusions are sparse. The purpose of this study was to evaluate the stability of results after facial growth and treatment with splints, Class III elastics, and chincup (SEC III) and to investigate the main determinants of relapse. Data from pretreatment, posttreatment, and long-term (at least 3 years after retention) serial cephalograms of 52 patients who received SEC III treatment were studied: only those with long-term data when growth had ceased (women over 18 and men over 21 years of age) were selected. At the end of the follow-up period (an average of 9 years), only 6 of the 52 patients had clinical relapse (overjet <or= 0). Low Wits appraisal, ANB angle, and overbite, and high SNB angle were the best predictors of relapse at the end of the treatment. Significantly greater decreases of the Wits appraisal and increases of ramus length during the follow-up were further associated with relapse. SEC III is a reliable treatment for skeletal Class III malocclusions. Long-term stability can be enhanced by a deeper overbite and the best possible skeletal correction. The results suggest that the correction occurs with no mandibular rotation but might be better with forward rotation.


ACL reconstruction: a meta-analysis of functional scores.
From individual randomized studies, it is unclear whether patellar tendon grafts or hamstring tendon grafts yield the best functional results after ACL reconstruction. Therefore, we performed a meta-analysis to provide quantitative data to compare patellar with hamstring grafts after ACL reconstruction with regard to knee function. We searched computerized databases for randomized controlled trials reporting one of the following outcomes related to function: final overall International Knee Documentation Committee score and return to preinjury level of activity. Studies were abstracted independently by two reviewers. Random effect models were used to pool the data. Fourteen trials (1263 patients) met the inclusion criteria. We found no difference in final overall International Knee Documentation Committee score or in the number of patients returning to full activity after patellar and hamstring graft reconstruction. Relative risk was 0.90 for final overall International Knee Documentation Committee Class A and 0.94 for return to preinjury level of activity in favor of patellar grafts. Quantitative interaction tests on the effect of treatment based on study quality, randomization status, number of strands used, and length of followup were non significant. At last followup, only 41% and 33% of patients, respectively, had patellar and hamstring grafts reconstructed reported as normal based on the final overall International Knee Documentation Committee score.


Impact of continuing professional development versus traditional continuing pharmacy education on learning behaviors.
To assess the effect of continuing professional development (CPD) on perceptions of learning behaviors compared with traditional continuing pharmacy education (CPE). Randomized controlled trial. Kaiser Permanente Colorado (KPCO) from August 2008 to June 2009. Licensed pharmacists employed at KPCO. After completing a basic CPD course, participants were randomized into a control group that continued with traditional CPE or an intervention group that completed three CPD workshops and used the CPD approach for their professional learning needs. At baseline and follow-up, all participants completed a study questionnaire on perceptions of their learning behaviors. Comparison of responses to questionnaire items at follow-up. 100 pharmacists were enrolled. The intervention (n = 44; 7 lost to follow-up) and control (n = 47; 2 lost to follow-up) groups were similar at baseline. At follow-up, a higher percentage of intervention than control participants reported changing their learning behaviors/activities sometimes (41% vs. 0%, P < 0.01) or frequently/always (18% vs. 4%, P < 0.05). More intervention than control participants responded that they frequently/always participated in learning by doing (61% vs. 36%, P < 0.05), identified specific learning objectives (93% vs. 30%, P < 0.01), and documented their learning plan (82% vs. 13%, P < 0.01). A higher percentage of intervention than control participants responded that they adhered to their learning plan partially/to a large extent (80% vs. 15%, P < 0.01) and more than three-quarters of the intervention participants responded that they partially/to a large extent achieved their learning objectives ( P < 0.01). Pharmacists who adopted a CPD approach were more likely to report that various aspects of their learning behaviors improved as a result of education activities compared with pharmacists who participated in traditional CPE.


Optimizing pulmonary rehabilitation in chronic obstructive pulmonary disease--practical issues: a Canadian Thoracic Society Clinical Practice Guideline.
Pulmonary rehabilitation (PR) participation is the standard of care for patients with chronic obstructive pulmonary disease (COPD) who remain symptomatic despite bronchodilator therapies. However, there are questions about specific aspects of PR programming including optimal site of rehabilitation delivery, components of rehabilitation programming, duration of rehabilitation, target populations and timing of rehabilitation. The present document was compiled to specifically address these important clinical issues, using an evidence-based, systematic review process led by a representative interprofessional panel of experts. The evidence reveals there are no differences in major patient-related outcomes of PR between nonhospital- (community or home sites) or hospital-based sites. There is strong support to recommend that COPD patients initiate PR within one month following an acute exacerbation due to benefits of improved dyspnea, exercise tolerance and health-related quality of life relative to usual care. Moreover, the benefits of PR are evident in both men and women, and in patients with moderate, severe and very severe COPD. The current review also suggests that longer PR programs, beyond six to eight weeks duration, be provided for COPD patients, and that while aerobic training is the foundation of PR, endurance and functional ability may be further improved with both aerobic and resistance training.


[Comparative study between plate-graft, cage-plate and peek cage in cervical arthrodesis for cervical stenosis].
A variety of systems have been developed to fix and perform arthrodesis of the cervical spine, with the advantages of reducing the risk of pseudoarthrosis, extrusion and graft collapse and achieving a more precise sagittal alignment. We therefore need to compare the results of the following approaches to patients with cervical stenosis: plate-graft, cage-plate and PEEK cage. Prospective, interventional, comparative trial involving three groups: group I, arthrodesis with plate-graft; group II, cage-plate, and group III, PEEK cage. The pre- and postoperative assessments included the cervical disability scale, the pain visual analog scale (VAS), and cervical spine X-rays. The results were analyzed with non-parametric tests such as the Wilcoxon sign test and the Kruskal-Wallis test for the comparison of more than two groups. Significance level was 0.05. The sample included a total of 37 patients: n = 12 in group I, with 22 levels; n = 11 in group II, with 19 levels, and n = 14 in group III, with 25 levels. Patient age ranged between 60 and 80. One year after surgery there was an improvement in cervical disability and the pain VAS score, with a statistically significant difference among the three groups (p = 0.001). However, radiographic measurements at that time showed a significant improvement in segmental lordosis (p = 0.02) only in plate-graft patients. The plate-graft approach provides better clinical and radiographic results compared to the cage-plate and PEEK cage techniques, at the one-year follow- up.


Inhibition of mTOR activity in diabetes mellitus reduces proteinuria but not renal accumulation of hyaluronan.
Accumulation of extracellular matrix (ECM) components is an early sign of diabetic nephropathy. Also the glycosaminoglycan hyaluronan (HA) is elevated in the renal interstitium during experimental diabetes. The mammalian target of rapamycin (mTOR) pathway participates in the signaling of hyperglycemia-induced ECM accumulation in the kidney, but this has not yet been investigated for HA. We hypothesized that interstitial HA accumulation during diabetes may involve mTOR activation. Diabetic rats (6 weeks post-streptozotocin (STZ)) were treated with rapamycin to inhibit mTOR or vehicle for 2 additional weeks. Kidney function (glomerular filtration rate, renal blood flow, urine output) and regional renal HA content were thereafter analyzed. The ability of the animals to respond to desmopressin was also tested. Diabetic animals displayed hyperglycemia, proteinuria, hyperfiltration, renal hypertrophy, increased diuresis with reduced urine osmolality, and reduced weight gain. Cortical and outer medullary HA was elevated in diabetic rats. Urine hyaluronidase activity was almost doubled in diabetic rats compared with controls. The ability to respond to desmopressin was absent in diabetic rats. Renal blood flow and arterial blood pressure were unaffected by the diabetic state. In diabetic rats treated with rapamycin the proteinuria was reduced by 32%, while all other parameters were unaffected. Regional renal accumulation of the ECM component HA is not sensitive to mTOR inhibition by rapamycin, while proteinuria is reduced in established STZ-induced diabetes. Whether the diabetes-induced renal accumulation of HA occurs through different pathways than other ECM components, or is irreversible after being established, remains to be shown.


Medical oncology workload, workforce census, and needs in Spain: two nationwide studies by the Spanish Society of medical oncology.
Growing complexity and demand for cancer care entail increased challenges for Medical Oncology (MO). The Spanish Society of Medical Oncology (SEOM) has promoted studies to provide updated data to estimate the need for medical oncologists in 2040 and to analyse current professional standing of young medical oncologists. Two national, online surveys were conducted. The first (2021) targeted 146 Heads of MO Departments, and the second (2022), 775 young medical oncologists who had completed their MO residency between 2014 and 2021. Participants were contacted individually, and data were processed anonymously. Participation rates reached 78.8% and 48.8%, respectively. The updated data suggest that 87-110 new medical oncologist full-time equivalents (FTEs) should be recruited each year to achieve an optimal ratio of 110-130 new cases per medical oncologist FTE by 2040. The professional standing analysis reveals that 9.1% of medical oncologists trained in Spain do not work in clinical care in the country, with tremendous employment instability (only 15.2% have a permanent contract). A high percentage of young medical oncologists have contemplated career paths other than clinical care (64.5%) or working in other countries (51.7%). Optimal ratios of medical oncologists must be achieved to tackle the evolution of MO workloads and challenges in comprehensive cancer care. However, the incorporation and permanence of medical oncologists in the national healthcare system in Spain could be compromised by their current sub-optimal professional standing.


Endocrine disruptive effects of cadmium on steroidogenesis: human adrenocortical carcinoma cell line NCI-H295R as a cellular model for reproductive toxicity testing.
Cadmium (Cd) is a known endocrine disruptor with the ability to affect the production of hormones involved in the regulation of reproductive processes. In this study human adrenocortical carcinoma cell line NCI-H295R was used as an in vitro biological model to study the effect of cadmium (CdCl2) on steroidogenesis. The cell cultures were exposed to different concentrations of CdCl2 (1.90, 3.90, 7.80, 15.60, 31.20 and 62.50 μM) and compared to control (medium without CdCl2). Cell viability was measured by the metabolic activity (MTT) assay for estimation of mitochondria structural integrity. Quantification of sexual steroid production directly from aliquots of the medium was performed by enzyme linked immunosorbent assay (ELISA). Following 48 h culture of the cells in the presence of CdCl2 a concentration-dependent depletion in progesterone production was observed at the lower concentrations of CdCl2. The lowest amount of progesterone was significantly detected in groups with the higher doses (≥ 31.20 μM) of CdCl2, which elicited significant (P < 0.01) cytotoxic action, too. Cadmium decreased testosterone release in the whole applied range even at the lower concentration of CdCl2. The release of 17β-estradiol decreased as well, but the decline was less pronounced compared to decrease of progesterone and testosterone. The cytotoxic effect was significantly (P < 0.01) detected at all concentrations of CdCl2 (1.90-62.50 μM) used in the study. However, the cell viability remained relatively high (>75%) up to 7.80 μM of CdCl2 and significantly (P < 0.01) decreased at 15.60 μM and higher concentrations of CdCl2. These results suggest that cadmium has endocrine disruptive effects on sexual steroid synthesis even at very low concentrations.


Effects of respiratory time ratio on heart rate variability and spontaneous baroreflex sensitivity.
Paced breathing is a frequently performed technique for cardiovascular autonomic studies. The relative timing of inspiration and expiration during paced breathing, however, is not consistent. We, therefore, examined whether indexes of heart rate variability and spontaneous baroreflex sensitivity would be affected by the respiratory time ratio that is set. We studied 14 healthy young adults who controlled their breathing rates to either 0.1 or 0.25 Hz in the supine and sitting positions. Four different inspiratory-to-expiratory time ratios (I/E) (uncontrolled, 1:1, 1:2, and 1:3) were examined for each condition in a randomized order. The results showed spectral indexes of heart rate variability and spontaneous baroreflex sensitivity were not influenced by the I/E that was set during paced breathing under supine and sitting positions. Porta's and Guzik's indexes of heart rate asymmetry were also not different at various I/E during 0.1-Hz breathing, but had larger values at 1:1 during 0.25-Hz breathing, although significant change was found in the sitting position only. At the same time, Porta's and Guzik's indexes obtained during 0.1-Hz breathing were greater than during 0.25-Hz breathing in both positions. The authors suggest that setting the I/E during paced breathing is not necessary when measuring spectral indexes of heart rate variability and spontaneous baroreflex sensitivity under the conditions used in this study. The necessity of paced breathing for the measurement of heart rate asymmetry, however, requires further investigation.


Alleged susceptibility of the elderly to infection.
The widely held notion, common in clinical medicine, that the elderly are more susceptible to infection is discussed critically. Implied but unstated in this sentiment is a premise that host defense mechanisms are less effective in the elderly, or that immune surveillance becomes defective with aging. No clear evidence exists to support these concepts; indeed, available information points to a normally functioning immune system in the elderly. An increased incidence of morbidity and mortality resulting from infection in the elderly does exist, however, and it is suggested that this stems from many of the functional and anatomical deficits which accompany the aging process and therefore predispose the elderly to infection. Examples of these degenerative problems are pulmonary hypoventilation, bronchopulmonary aspiration, immobility, and urinary retention. These conditions can predispose the elderly to infection by common extracellular microorganisms that are the normal flora of the mucosal and skin surfaces of the body. More precise information on the nature of injuries caused by these organisms in the elderly and on the causes of the resulting higher mortality rates in the elderly is required before an increased incidence of infection in the elderly can be attributed to an increase in their susceptibility to infection because of defective immune or host defense mechanisms.


Mannose-resistant hemagglutination of human erythrocytes by enterotoxigenic Escherichia coli with colonization factor antigen II.
The human erythrocyte receptor which mediates mannose-resistant hemagglutination by enterotoxigenic Escherichia coli possessing colonization factor antigen II is not universally distributed among donors. Mannose-resistant hemagglutination-positive erythrocytes are more common among black donors than nonblack donors; tests with erythrocytes of known antigenic makeup confirm this correlation. Colonization factor antigen II receptor activity of mannose-resistant hemagglutination-positive erythrocytes is unstable when whole blood is stored at 4 degrees C. Also, screening of donors is best performed with enterotoxigenic E. coli possessing colonization factor antigen II composed of the coli surface antigen 1 (CS1) plus CS3, since these consistently produce stronger hemagglutination reactions than strains with colonization factor antigen II composed of either CS2 plus CS3 or CS3 only.


P-Selectin support of neonatal neutrophil adherence under flow: contribution of L-selectin, LFA-1, and ligand(s) for P-selectin.
To further define the neonatal neutrophil's ability to localize to inflamed tissue compared with adult cells, we examined the neonatal neutrophil interactions with P-selectin monolayers under two conditions: (1) attachment under constant shear stress and flow and (2) detachment where cells were allowed to attach in the absence of shear stress and then shear stress is introduced and increased in step-wise increments. Cord blood and adult neutrophils had minimal interactions with unstimulated human umbilical vein endothelial cells (HUVECs) at a constant shear stress of 2 dynes/cm2. There was a marked increase in the number of both neonatal and adult cells interacting (interacting cells = rolling + arresting) with HUVECs after histamine stimulation, although the neonatal value was only 40% of adult (P < .05). Neonatal neutrophils also had significantly decreased interaction with monolayers of Chinese hamster ovary (CHO) cells transfected with human P-selectin (CHO-P-selectin; 60% of adult values, P < .003). Of the interacting cells, there was a lower fraction of neonatal cells that rolled compared with adult cells on both stimulated HUVECs and CHO-P-selectin. That neonatal neutrophil L-selectin contributes to the diminished attachment to P-selectin is supported by the following: (1) Neonatal neutrophils had significantly diminished expression of L-selectin. (2) Anti-L-selectin monoclonal antibody reduced the number of interacting adult neutrophils to the level seen with untreated neonatal neutrophils, but had no effect on neonatal neutrophils. In contrast, L-selectin appeared to play no role in maintaining the interaction of either neonatal or adult neutrophils in the detachment assay. Once attachment occurred, the neonatal neutrophil's interaction with the P-selectin monolayer was dependent on LFA-1 and to other ligands to a lesser degree based on the following: (1) Control neonatal neutrophils had decreased rolling fraction compared with adult neutrophils, although the total number of interacting neutrophils was equal between groups. (2) Anti-LFA-1 treatment resulted in an increase in the rolling fraction of both neonatal and adult neutrophils. However, whereas the number of interacting adult neutrophils remained unchanged, the number of neonatal neutrophils decreased with increased shear stress. We speculate that this increased detachment of neonatal cells is due to differences in neutrophil ligand(s) for P-selectin.


Viola cornuta and Viola x wittrockiana: Phenolic compounds, antioxidant and neuroprotective activities on Caenorhabditis elegans.
Different Viola species are known for their traditional use as analgesic, antitussive, febrifuge, hipnotic, analgesic and anti-inflammatory medicinal agents. Additionally, they are considered edible flowers in certain cultures. Thus, the aim of this work was to characterize the phenolic composition and to assess the neuroprotective properties of Viola cornuta and Viola x wittrockiana using in vitro and in vivo methodologies with Caenorhabditis elegans as model. The identification of the phenolic compounds was carried out with a LC-DAD-ESI/MSn. The antioxidant activity of the extracts was determined in vitro using Folin- Ciocalteu, DPPH and FRAP assays and in vivo with a juglone-induced oxidative stress in C. elegans. The neuroprotective properties were evaluated measuring the ability to inhibit CNS enzymes (MAO A, AChE), and the capability to avoid paralyzing the C. elegans CL4176, an Alzheimer disease model. The phenolic content was higher in V. x wittrockiana, being quercetin-3-O-(6-O-rhamnosylglucoside)-7-O-rhamnoside the predominant compound in the extract, which also exhibited a stronger antioxidant capacity in vitro and a higher response to lethal oxidative stress on C. elegans than V. cornuta. Only V. x wittrockiana showed inhibitory effect on CNS enzymes, such as acetylcholinesterase and monoamine oxidase A, but both had protective effect against the paralysis of C. elegans. These findings suggest that the studied V. cornuta and V. x wittrockiana could be interesting candidates for age related neurodegenerative disorder associated with oxidative stress.


Identification of oligopeptide binding to colon cancer cells separated from patients using laser capture microdissection.
The development of intravascular conjugates that efficiently deliver genes or drugs to tumors is limited by the lack of efficacious targeting ligands. Small targeting peptides, such as those iterated by phage display technology, offer enormous potential for these applications. The majority of reports published to date have focused on the identification of peptides isolated for their ability to bind to human cancer cell lines in vitro, and have failed to account for the loss of polarization and de-differentiation of such cells from their in vivo state. Here, we report a novel approach for the identification of peptides capable of binding specifically to cancer cells derived from clinically resected human colon cancer. In this strategy, laser capture microdissection (LCM) is performed on a surgically resected colon cancer specimen to separate only cancer cells from the specimen. Subsequently, biopanning was performed on the LCM-selected colon cancer cells to identify peptide sequences that bound specifically to them. A peptide containing the SPT motif was selected as the most promising consensus sequence binding specifically to the LCM-selected colon cancer cells. Phage clones displaying the SPT motif demonstrated 9-fold higher binding to colon cancer cells derived from a patient than insertless phage (p < 0.05), while, recovery of the SPT phage from the colon cancer cell lines DLD-1 and HCT-15 was 7-fold higher than that of the control insertless phage (p < 0.05). The binding of SPT phage to colon cancer cells from the patient was confirmed by immunofluorescence. Additionally, a synthesized SPT-containing peptide (SPTKSNS) showed binding activity in the absence of mitogenic effects on colon cancer cells in vitro. In summary, we have introduced LCM into a biopanning procedure and identified a small peptide that binds preferentially to colon cancer cells derived from a clinically resected sample. This procedure could be applicable for the design of customized cancer cell targeting methodologies using clinical biopsy samples from human subjects.


Early pregnancy soluble E-selectin concentrations and risk of preeclampsia.
Circulating biomarkers of endothelial dysfunction and inflammation are elevated in late pregnancy in women with preeclampsia. We examined plasma levels of inflammatory cytokines and adhesion molecules in early pregnancy, to assess their ability to predict preeclampsia. In a prospective longitudinal study, 2600 women with singleton pregnancies and no history of hypertension were recruited at their antenatal hospital (booking) visit at gestational week 12-16. Of these, 49 (1.9%) developed preeclampsia, whereas 74 women matched for age and BMI with uncomplicated pregnancies were selected as controls. A subset of women with risk factors for preeclampsia were sampled again at gestational weeks 16 and 28 (11 cases, 39 controls) and postnatally (six cases, 36 controls). From multiplex analysis, soluble E-selectin concentrations were higher at 12-16 weeks in women who subsequently developed preeclampsia (15.1 ± 4.9 versus 12.9 ± 4.5 ng/ml, P = 0.02). At gestational week 28, E-selectin concentrations were again higher in women who went on to develop preeclampsia compared with controls (14.4 ± 5.6 versus 10.7 ± 3.5 ng/ml, P = 0.010), whereas levels were not different between the two groups in postpartum samples. Changes in soluble E-selectin concentration in early pregnancy may reflect underlying pathophysiological processes, potentially providing mechanistic insights into preeclampsia.


Influence of parental socioeconomic status on caries prevalence among children seen at the university college hospital, ibadan.
Dental caries is a lifetime disease and its sequelae have been found to constitute health problems of immense proportion in children. Environmental factors such as culture, socioeconomic status, lifestyle and dietary pattern can have a great impact on cariesresistance or caries-development in a child. The present study was conducted to evaluate the relationship between dental caries and socioeconomic status of children attending paediatric dental clinic in UCH Ibadan. Socio-demographic data for each child that attended paediatric dental clinic, UCH Ibadan within a period of one year was obtained and recorded as they presented in the dental clinic, followed by oral examination for each of them in the dental clinic to detect decayed, missing and filled deciduous and permanent teeth (dmft and DMFT respectively). The mean dmft and DMFT score for the 209 children seen within period of study were 1.58 ± 2.4 and 0.63+1.3 respectively. Highest caries prevalence (46.9%) was found within the high social class while the caries prevalence in middle and low social class were 40.5% and 12.6% respectively. The highest dmft/DMFT of >7 was recorded in two children belonging to high social class. The difference in dmft in the three social classes was statistically significant (x 2 = 51.86,p= 0.008) but for DMFT, it was not statistically significant (x2 = 6.92, p = 0.991). Caries experience was directly related to socio-economic status of the parents of the studied children with highest caries prevalence in high and middle socioeconomic classes.


Interaction of Epstein-Barr virus nuclear antigen leader protein (EBNA-LP) with HS1-associated protein X-1: implication of cytoplasmic function of EBNA-LP.
Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNA-LP) consists of W1W2 repeats and a unique C-terminal Y1Y2 domain and has been suggested to play an important role in EBV-induced transformation. To identify the cellular factors interacting with EBNA-LP, we performed a yeast two-hybrid screen, using EBNA-LP cDNA containing four W1W2 repeats as bait and an EBV-transformed human peripheral blood lymphocyte cDNA library as the source of cellular genes. Our results were as follows. (i) All three cDNAs in positive yeast colonies were found to encode the same cellular protein, HS1-associated protein X-1 (HAX-1), which is localized mainly in the cytoplasm and has been suggested to be involved in the regulation of B-cell signal transduction and apoptosis. (ii) Mutational analysis of EBNA-LP revealed that the association with HAX-1 is mediated by the W1W2 repeat domain. (iii) A purified chimeric protein consisting of glutathione S-transferase fused to EBNA-LP specifically formed complexes with HAX-1 transiently expressed in COS-7 cells. (iv) When EBNA-LP and HAX-1 were coexpressed in COS-7 cells, EBNA-LP was specifically coimmunoprecipitated with HAX-1. (v) Careful cell fractionation experiments of an EBV-infected lymphoblastoid cell line revealed that EBNA-LP is localized in the cytoplasm as well as in the nucleus. (vi) When EBNA-LP containing four W1W2 repeats was expressed in COS-7 cells, EBNA-LP was detected mainly in the nucleus by immunofluorescence assay. Interestingly, when EBNA-LP containing a single W1W2 repeat was expressed in COS-7 cells, EBNA-LP was localized predominantly in the cytoplasm and was colocalized with HAX-1. These results indicate that EBNA-LP is in fact present and may have a significant function in the cytoplasm, possibly by interacting with and affecting the function of HAX-1.


[90th anniversary of national hygienic regulation of chemicals in workplace air].
The authors followed occurrence and formation of the national hygienic regulation of chemicals in workplace air, since 1920s in historical aspect. Now there is 90th anniversary of the regulation.


Insulin-like growth factor (IGF) performance in ovarian function and applications in reproductive biotechnologies.
The role of the insulin-like growth factor (IGF) system has attracted close attention. The activity of IGF binding proteins (IGFBPs) within the ovary has not been fully elucidated to date. These proteins bind to IGF with an equal, or greater, affinity than to the IGF1 receptor, thus being in the main position to regulate IGF signalling, in addition to extending the half-life of IGFs within the bloodstream and promoting IGF storage in specific tissue niches. IGF1 has an important part in cell proliferation, differentiation and apoptosis. Considering the importance of IGFs in oocyte maturation, this review sought to elucidate aspects including: IGF production mechanisms; constituent members of their family and their respective functions; the role that these factors play during folliculogenesis, together with their functions during oocyte maturation and apoptosis, and their performance during luteal development. This review also explores the role of IGFs in biotechnological applications, focusing specifically on animal genetic gain.


Selenium and selenoproteins in mammals: extraordinary, essential, enigmatic.
Selenium (Se), once known only for its potential toxicity, is now well established as an essential trace element for mammals. Insufficient Se intake predisposes to and manifests in a variety of diseases. Recent studies have proven that it is the synthesis of selenocysteine (Sec)-containing proteins, designated selenoproteins, which represents an essential prerequisite for regular development and a long and healthy life. New transgenic mouse models analysing those selenoproteins with proven enzymatic functions displayed particular phenotypes and highlighted essential Se-dependent processes in development, growth or against specific challenges. While there is a growing molecular understanding of and general agreement on the importance of sufficiently high Se intake and undisturbed selenoprotein biosynthesis, many of the recently identified selenoproteins are still uncharacterised, and the effects and consequences of supra-physiological Se dosages are not biochemically understood. With the recent definition of the human and mouse selenoproteomes and a growing number of available tools, the Se field is now geared for a great leap forward. Se biology has already broadened our knowledge about the genetic code and about protein translation. It now holds great promises also for a better understanding of some key aspects of cancer, inflammation, fertility and prevention of age-associated diseases.


[Direct-action mutagens in exhausts of vehicles with diesel engines].
The genotoxic activity of exhausts from one-shaft gas-turbine GTE-5 engine (30 kW) and a standard D-54A diesel (40 kW) have been studied. Thus, the extracts of soot from GTE-5 and D-54A induced reversions in Salmonella typhimurium both with and without metabolic activation: furthermore, extracts of soot from GTE-5 demonstrated a higher mutagenic activity. The direct mutagenic effect of the exhausts depended neither on the presence of BP nor on the other polycyclic aromatic hydrocarbons (PAHs). Most probably, it was connected with the presence of nitro-PAHs. The need for studying the PAH content in vehicle engines' exhausts and for taking into account their effect in the control and standardization is established.


The sedative effect of non-alcoholic beer in healthy female nurses.
The hop (Humulus lupulus L.), a component of beer, is a sedative plant whose pharmacological activity is principally due to its bitter resins, in particular to the α-acid degradation product 2-methyl-3-buten-2-ol. The mechanism of action of hop resin consists of raising the levels of the neurotransmitter γ-aminobutyric acid (GABA), an inhibitory neurotransmitter acting in the central nervous system (CNS). To analyze the sedative effect of hops as a component of non-alcoholic beer on the sleep/wake rhythm in a work-stressed population. The experiment was conducted with healthy female nurses (n = 17) working rotating and/or night shifts. Overnight sleep and chronobiological parameters were assessed by actigraphy (Actiwatch®) after moderate ingestion of non-alcoholic beer containing hops (333 ml with 0.0% alcohol) with supper for 14 days (treatment). Data were obtained in comparison with her own control group without consumption of beer during supper. Actigraphy results demonstrated improvement of night sleep quality as regards the most important parameters: Sleep Latency diminished (p≤0.05) in the Treatment group (12.01±1.19 min) when compared to the Control group (20.50±4.21 min), as also did Total Activity (p≤0.05; Treatment group = 5284.78±836.99 activity pulses vs Control = 7258.78±898.89 activity pulses). In addition, anxiety as indexed by the State-Trait Anxiety Inventory (STAI) decreased in the Treatment group (State Anxiety 18.09±3.8 vs Control 20.69±2.14). The moderate consumption of non-alcoholic beer will favour night-time rest, due in particular to its hop components, in addition to its other confirmed benefits for the organism.


SMC complexes: Lifting the lid on loop extrusion.
Loop extrusion has emerged as a prominent hypothesis for how SMC complexes shape chromosomes - single molecule in vitro observations have yielded fascinating images of this process. When not extruding loops, SMC complexes are known to topologically entrap one or more DNAs. Here, we review how structural insight into the SMC complex cohesin has led to a molecular framework for both activities: a Brownian ratchet motion, associated with topological DNA entry, might repeat itself to elicit loop extrusion. After contrasting alternative loop extrusion models, we explore whether topological loading or loop extrusion is more adept at explaining in vivo SMC complex function. SMC variants that experimentally separate topological loading from loop extrusion will in the future probe their respective contributions to chromosome biology.


Sudden infant deaths in sitting devices.
As episodes of decreased oxygenation levels have been recorded in premature infants placed in car seats, it is believed that these infants are at risk of life-threatening events and death. No data on the prevalence of such infant deaths are available. The aim of our study was to determine the incidence of sudden deaths in infants occurring in sitting devices in a whole population and to determine whether premature infants account for a disproportionate number of these deaths. Retrospective population-based cohort study reviewing all cases of sudden unexpected death in infants between birth and 1 year of age that occurred in the province of Quebec between January 1991 and December 2000. Of the 508 deaths reviewed, 409 were unexplained and 99 were explained after investigation. Seventeen deaths occurred in a sitting device, of which 10 were unexplained. There was no excess of premature infants dying. However, there was an excess of infants of less than 1 month of age found to have died in a sitting position in the unexplained death group. In addition, three infants who died in a sitting position had an increased risk of upper airway obstruction. Although very few deaths occurred in car seats, our results suggest that caution should be used when placing younger infants in car seats and similar sitting devices, whether the infants have been born prematurely or not. We also recommend that more attention be given to infants at increased risk of upper airway obstruction.


Conversations about mental states and theory of mind development during middle childhood: A training study.
Despite 30years of productive research on theory of mind (ToM), we still know relatively little about variables that influence ToM development during middle childhood. Recent experimental studies have shown that conversations about the mind affect ToM abilities, but they have not explored the mechanisms underlying this developmental effect. In the current study, we examined two potential mechanisms through which conversations about mental states are likely to influence ToM: an increased frequency of references to mental states when explaining behavior and an increased accuracy of mental-state attributions. To this aim, we conducted a training study in which 101 children were assigned to either an intervention condition or a control condition. The conversation-based intervention was made up of four sessions scheduled over 2weeks. Children completed a battery of assessments before and after the intervention as well as 2months later. The groups were equivalent at Time 1 (T1) for age, family affluence, vocabulary, and executive functions. The ToM group showed an improvement in ToM skills (as evaluated on both the practiced tasks and a transfer task). Mediation analyses demonstrated that the accuracy of mental-state attributions, but not the mere frequency of mental-state references, mediated the positive effect of conversations about the mind on ToM development. Our results indicate that conversational experience can enhance mental-state reasoning not by simply drawing children's attention to mental states but rather by scaffolding a mature understanding of social situations.


Revised Escherichia coli selenocysteine insertion requirements determined by in vivo screening of combinatorial libraries of SECIS variants.
To investigate the stringency of the Escherichia coli selenocysteine insertion sequence (SECIS) requirements, libraries of SECIS variants were screened via a novel method in which suppression of the selenocysteine (Sec) opal codon was coupled to bacteriophage plaque formation. The SECIS variant libraries were designed with a mostly paired lower stem, so that randomization could be focused on the upper stem and loop regions. We identified 19 functional non-native SECIS sequences that violated the expected pairing requirements for the SECIS upper stem. All of the SECIS variants were shown to permit Sec insertion in phage (by chemical modification of the Sec residue) and fused to lacZalpha (by beta-galactosidase assay). The diminished pairing of the upper stem appears to be mitigated by the overall stem stability; a given upper stem variant has significantly higher readthrough in the context of a paired, rather than unpaired, lower stem. These results suggest an unexpected downstream sequence flexibility in prokaryotic selenoprotein expression.


Antipsychotic and benzodiazepine use among nursing home residents: findings from the 2004 National Nursing Home Survey.
To document the extent and appropriateness of use of antipsychotics and benzodiazepines among nursing home residents using a nationally representative survey. Cross-sectional analysis of the 2004 National Nursing Home Survey. Bivariate and multivariate analyses examined relationships between resident and facility characteristics and antipsychotic and benzodiazepine use by appropriateness classification among residents aged 60 years and older (N = 12,090). Resident diagnoses and information about behavioral problems were used to categorize antipsychotic and benzodiazepine use as appropriate, potentially appropriate, or having no appropriate indication. More than one quarter (26%) of nursing home residents used an antipsychotic medication, 40% of whom had no appropriate indication for such use. Among the 13% of residents who took benzodiazepines, 42% had no appropriate indication. In adjusted analyses, the odds of residents taking an antipsychotic without an appropriate indication were highest for residents with diagnoses of depression (odds ratio [OR] = 1.31; 95% confidence interval [CI]: 1.12-1.53), dementia (OR = 1.82; 95% CI: 1.52-2.18), and with behavioral symptoms (OR = 1.97, 95% CI: 1.56-2.50). The odds of potentially inappropriate antipsychotic use increased as the percentage of Medicaid residents in a facility increased (OR = 1.08, 95% CI: 1.02-1.15) and decreased as the percentage of Medicare residents increased (OR = 0.46, 95% CI: 0.25-0.83). The odds of taking a benzodiazepine without an appropriate indication were highest among residents who were female (OR = 1.44; 95% CI: 1.18-1.75), white (OR = 1.95; 95% CI: 1.47-2.60), and had behavioral symptoms (OR = 1.69; 95% CI: 1.41-2.01). Antipsychotics and benzodiazepines seem to be commonly prescribed to residents lacking an appropriate indication for their use.


Lattice-Boltzmann-Langevin simulations of binary mixtures.
We report a hybrid numerical method for the solution of the Model H fluctuating hydrodynamic equations for binary mixtures. The momentum conservation equations with Landau-Lifshitz stresses are solved using the fluctuating lattice Boltzmann equation while the order parameter conservation equation with Langevin fluxes is solved using stochastic method of lines. Two methods, based on finite difference and finite volume, are proposed for spatial discretization of the order parameter equation. Special care is taken to ensure that the fluctuation-dissipation theorem is maintained at the lattice level in both cases. The methods are benchmarked by comparing static and dynamic correlations and excellent agreement is found between analytical and numerical results. The Galilean invariance of the model is tested and found to be satisfactory. Thermally induced capillary fluctuations of the interface are captured accurately, indicating that the model can be used to study nonlinear fluctuations.


Biology of the adenomatous polyposis coli tumor suppressor.
The adenomatous polyposis coli (APC) gene was first identified as the gene mutated in an inherited syndrome of colon cancer predisposition known as familial adenomatous polyposis coli (FAP). Mutation of APC is also found in 80% of all colorectal adenomas and carcinomas and is one of the earliest mutations in colon cancer progression. Similar to other tumor suppressor genes, both APC alleles are inactivated by mutation in colon tumors, resulting in the loss of full-length protein in tumor cells. The functional significance of altering APC is the dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, which include cell cycle progression, migration, differentiation, and apoptosis. Roles for APC in some of these processes are in large part attributable to its ability to regulate cytosolic levels of the signaling molecule beta-catenin and to affect the transcriptional profile in cells. This article summarizes numerous genetic, biochemical, and cell biologic studies on the mechanisms of APC-mediated tumor suppression. Mouse models of FAP, in which the APC gene has been genetically inactivated, have been particularly useful in testing therapeutic and chemopreventive strategies. These data have significant implications for colorectal cancer treatment approaches as well as for understanding other disease genes and cancers of other tissue types.


Recurrent transcriptional clusters in the genome of mouse pluripotent stem cells.
A number of studies have shown that transcriptome analysis in terms of chromosomal location can reveal regions of non-random transcriptional activity within the genome. Genomic clusters of differentially expressed genes can identify genomic patterns of structural organization, underlying copy number variations or long-range epigenetic regulation such as X-chromosome inactivation. Here we apply an integrative bioinformatics analysis to a collection of 315 freely available mouse pluripotent stem cell samples to discover transcriptional clusters in the genome. We show that over half of the analysed samples (56.83%) carry whole or partial-chromosome spanning clusters which recur in genomic regions previously implicated in chromosomal imbalances. Strikingly, we found that the presence of such large-clusters is linked to the differential expression of a limited number of genes, common to all samples carrying clusters irrespectively of the chromosome where the cluster is found. We have used these genes to train and test classification models that can predict samples that carry large-scale clusters on any chromosome with over 90% accuracy. Our findings suggest that there is a common downstream activation in these cells that affects a limited number of nodes. We propose that this effect is linked to selective advantage and identify potential driver genes.


The Danish neonatal clinical database is valuable for epidemiologic research in respiratory disease in preterm infants.
We examined the quality of the information on the use of surfactant and the use of and duration of nasal continuous positive airway pressure (nCPAP), oxygen supplementation, and mechanical ventilation in the Danish Neonatal Clinical Database (NeoBase). We included all neonates born with a gestational age < 32 weeks admitted to a Neonatal Intensive Care Unit (NICU) at two university hospitals in 2005. On discharge, the clinicians complete a structured form with information related to the delivery and course of stay in the NICU. These forms were entered into the NeoBase. The nurses' daily bedside documentation was used as reference standard. Concordance was used as a measure of agreement between the NeoBase and the reference standard. For the dichotomous variables the concordance was defined as the sensitivity of the information registered in the NeoBase. For the continuous variables, it was based on the discrepancy in days between the NeoBase and the reference standard. The percentage of concordance was described as high (> 90), moderate (70-90) or low (< 70). Overall, 153 infants participated in the study. Concordance was high for all dichotomous variables. The NeoBase slightly underestimated the duration of nCPAP and mechanical ventilation. The duration of oxygen therapy was neither over- nor underestimated in the NeoBase. Concordance was low for all continuous variables if we assumed that the registered information was identical. It was 100% for duration of mechanical ventilation and moderate for nCPAP and oxygen supplementation if we allowed for a discrepancy of 1 day. The NeoBase is a valuable tool for clinical and epidemiologic research and quality assurance regarding neonatal respiratory disease.


Cold Atmospheric Pressure Plasma: A Growing Paradigm in Diabetic Wound Healing-Mechanism and Clinical Significance.
Diabetes is one of the most significant causes of death all over the world. This illness, due to abnormal blood glucose levels, leads to impaired wound healing and, as a result, foot ulcers. These ulcers cannot heal quickly in diabetic patients and may finally result in amputation. In recent years, different research has been conducted to heal diabetic foot ulcers: one of them is using cold atmospheric pressure plasma. Nowadays, cold atmospheric pressure plasma is highly regarded in medicine because of its positive effects and lack of side effects. These conditions have caused plasma to be considered a promising technology in medicine and especially diabetic wound healing because studies show that it can heal chronic wounds that are resistant to standard treatments. The positive effects of plasma are due to different reactive species, UV radiation, and electromagnetic fields. This work reviews ongoing cold atmospheric pressure plasma improvements in diabetic wound healing. It shows that plasma can be a promising tool in treating chronic wounds, including ones resulting from diabetes.


Prevalence of sleep disturbances during COVID-19 outbreak in an urban Chinese population: a cross-sectional study.
The COVID-19 pandemic is a large-scale public health emergency that likely precipitated sleep disturbances in the community. This study aimed to investigate the prevalence and correlates of sleep disturbances during the early phase of COVID-19 pandemic. This web-based cross-sectional study recruited 1138 Hong Kong adults using convenience sampling over a two-week period from 6th April 2020. The survey collected data on sleep disturbances, mood, stress, stock of infection control supplies, perceived risk of being infected by COVID-19, and sources for acquiring COVID-19 information. The participants were asked to compare their recent sleep and sleep before the outbreak. The Insomnia Severity Index (ISI) was used to assess their current insomnia severity. Prevalence was weighted according to 2016 population census. The weighted prevalence of worsened sleep quality, difficulty in sleep initiation, and shortened sleep duration since the outbreak were 38.3%, 29.8%, and 29.1%, respectively. The prevalence of current insomnia (ISI score of ≥10) was 29.9%. Insufficient stock of masks was significantly associated with worsened sleep quality, impaired sleep initiation, shortened sleep duration, and current insomnia in multivariate logistic regression (adjusted OR = 1.57, 1.72, 1.99, and 1.96 respectively, all p < 0.05). A high proportion of people in Hong Kong felt that their sleep had worsened since the COVID-19 outbreak. Insufficient stock of masks was one of the risk factors that were associated with sleep disturbances. Adequate and stable supply of masks may play an important role to maintain the sleep health in the Hong Kong general population during a pandemic outbreak.


[Complicated duodeno-biliary fistula in bleeding duodenal ulcer: case report an literature review].
Upper gastrointestinal tract bleedings may represent the first clinical evidence of peptic ulcer and the related surgical emergency is still characterized by a high mortality rate. The presence of multiple complications, rare but possible in case of duodenal ulcer, such as the fistulization in the common bile duct alone or associated to others, can significantly increase the difficulty in the treatment. The Authors report a particularly complex case of a 77 years old male diabetic patient, with chronic bronchopaty, urgently admitted to our department for hematemesis. Soon after his hemodynamic stabilization, the patient was submitted to surgery which showed a duodenal ulcer with penetration/fistulization in the common bile duct associated to a perforation of the gallbladder with intra-hepatic abscess and erosion of the gastro-duodenal artery. Despite unfavourable outcome the case gave us the starting point for a review of the literature primarily related to the rarer biliary complications of duodenal ulcer. Bleeding ulcers today are usually treated by an interdisciplinary approach comprehensive of endoscopy, interventional radiology and, only rarely, surgery. The choice among the available options depends on the clinical presentation of the patient. Despite diagnostic and therapeutic progresses, peptic ulcer may still rarely have a dramatic presentation and be associated to uncommon and difficult anatomical aspects whose diagnosis and treatment may be not easy at all. The knowledge of all the aspects of peptic ulcer pathophysiology is therefore essential for the treatment of these patients.


Tumour necrosis factor-alpha production in human alveolar macrophages: modulation by inhaled corticosteroid.
Using an ex vivo alveolar macrophage model, the hypothesis that inhaled preparations of corticosteroids might have important anti-inflammatory effects on cells of the peripheral airway was tested. The tumour necrosis factor (TNF)-alpha-inducing potential of three glycolipid preparations from nonpathogenic (arabinofuranasyl lipoarabinomannan (LAM (Ara-LAM)) and virulent (mannase LAM (ManLAM)) mycobacteria and Gram-negative bacteria (lipopolysaccharide (LPS)), in primary alveolar macrophage preparations was investigated. A novel inhaled chlorofluorocarbon (CFC)-free preparation of beclomethasone dipropionate (hydrofluoroalkane 134a (HFA)-BDP) with increased peripheral lung deposition was investigated for its ability to modulate glycolipidinduced TNF-alpha production by human alveolar macrophages, in comparison with a CFC-containing preparation and placebo. Compared to the basal TNF-alpha bioactivity of 0.72 ng x mL-1 (geometric mean), the TNF-alpha bioactivity in the macrophage preparation increased following incubation with LPS (138 ng x mL-1, p<0.001), AraLAM (12.6 ng-mL-1, p<0.001) and ManLAM (1.42 ng x mL-1, p=0.02). HFA-BDP, administered in vivo, significantly reduced LPS- and ManLAM-induced TNF-alpha production by alveolar macrophages cultured ex vivo. No change in glycolipid-induced TNF-alpha production was observed following in vivo administration of CFC-BDP or HFA-placebo. This is the first demonstration of an immunomodulatory effect on alveolar cells of corticosteroid delivered via metered dose inhaler. The present findings suggest that alveolar deposition of beclomethasone dipropionate is capable of modulating the inflammatory potential of the alveolar macrophage population.


NIT-1, a pancreatic beta-cell line established from a transgenic NOD/Lt mouse.
NOD/Lt mice harboring a hybrid rat insulin-promoter/SV40 large T-antigen gene spontaneously develop beta-cell adenomas. NIT-1 is a pancreatic beta-cell line established from one of these transgenic mice. Immunocytochemical staining of passage 18 cells showed most contained insulin, with less than 5% containing glucagon, and none containing pancreatic polypeptide or somatostatin. Glucagon content radioimmunoassayed in cell extracts was only 0.27% of the insulin content. Two-hour insulin secretion at 16.5 mM glucose was 638 ng/10(6) cells (41% of intracellular content) compared to only 1.3 ng glucagon (32% of intracellular content). Stimulated insulin secretion was consistently observed in response to 11 and 16.5 mM glucose between passages 11 and 19. At passage 19, both theophylline and tolbutamide stimulated insulin secretion at 5.5 mM glucose. Northern-blot analysis confirmed high levels of insulin mRNA but only trace glucagon mRNA and undetectable somatostatin mRNA. Interferon-gamma (IFN-gamma)-induced MHC class I RNA expression was correlated with markedly increased antigen expression at the cell surface. Similarly, a MHC-linked "occult" class I-like antigen detected by Cr release assay only after exposure of standard NOD/Lt islet cells to IFN-gamma was strongly induced by IFN-gamma in NIT-1 cells. Cell surface MHC class II antigen was not constitutively expressed on NIT-1 cells and could not be detected after IFN-gamma incubation, despite demonstration of IFN-gamma-induced Aa, Ab, and Li invariant-chain RNA transcripts. Similarly IFN-gamma induction of intercellular adhesion molecule 1 (Icam-1) transcripts was not accompanied by demonstrable cell surface expression of ICAM-1 antigen.(ABSTRACT TRUNCATED AT 250 WORDS)


ASTRONOMY: Enhanced: Water's Role in Making Stars.
Water has long been believed to play an important role in star-forming regions as an oxygen reservoir and by cooling the circumstellar gas cloud, but observational evidence has been hard to come by. In her Perspective, Nisini explains how recent satellite missions have provided the first observational evidence that allows chemical models of star formation to be tested. Water is found to be initially low in abundance but to increase in abundance once a protostar has formed. The observations include protostars that are the precursors of sunlike stars, thus shedding light on water production in solar-type systems.


Understanding depressive rumination from a cognitive science perspective: the impaired disengagement hypothesis.
Persisting negative thoughts are considered a hallmark of depression. Recent information-processing approaches have begun to uncover underlying mechanisms of depressive rumination. Despite marked advances in this area, there is a lack of integration between psychopathology and cognitive (neuro) science research. We propose the 'impaired disengagement' hypothesis as a unifying framework between both approaches. The core tenet of our model is that prolonged processing of self-referent material is due to impaired attentional disengagement from negative self-referent information. We discuss empirical evidence for this framework and outline future ways in which the causal predictions of this model can be tested. The proposed framework can account for effectiveness of various treatments for depression and may aid in devising new interventions to target depressive cognition.


Effects of a Cognitive Behavioral Digital Therapeutic on Anxiety and Depression Symptoms in Patients With Cancer: A Randomized Controlled Trial.
Patients with cancer often experience elevated levels of distress. This double-blind, randomized controlled trial compared the impact of an app-based version of cognitive behavioral stress management (CBSM) versus a health education sham app on anxiety and depression symptoms. Patients with nonmetastatic (stage I-III) cancer who were receiving or recently completed (≤6 months) systemic treatment were recruited nationwide. The primary outcome of change in anxiety symptoms (PROMIS-Anxiety) over 12 weeks and the top secondary outcome of change in depression symptoms (PROMIS-Depression) over 12 weeks were analyzed using mixed-effects modeling with repeated measures (weeks 0, 4, 8, 12). Patient global impressions of change in anxiety and depression were reported at weeks 4, 8, and 12. In addition, self-reported adverse events were collected throughout the study and adjudicated by the site principal investigator. Four hundred forty-nine patients were enrolled in the trial (age M [standard deviation] = 52.44 [11.46]; 81% female; 76% White; 53% breast cancer). Patients randomly assigned to digitized CBSM showed significantly greater reductions in anxiety (B = -0.03; P = .019) and depression (B = -0.02; P = .042) symptoms over 12 weeks. Patients who received digitized CBSM were also significantly more likely to perceive much or very much improvement (v no/minimal change or much/very much worse) in their symptoms of anxiety (χ2 = 31.76; P < .001) and depression (χ2 = 19.70; P < .001) compared with the control. The use of digitized CBSM led to significant improvements in anxiety and depression outcomes compared with the sham app.


Natural variation in the microcystin synthetase operon mcyABC and impact on microcystin production in Microcystis strains.
Toxic Microcystis strains often produce several isoforms of the cyclic hepatotoxin microcystin, and more than 65 isoforms are known. This has been attributed to relaxed substrate specificity of the adenylation domain. Our results show that in addition to this, variability is also caused by genetic variation in the microcystin synthetase genes. Genetic characterization of a region of the adenylation domain in module mcyB1 resulted in identification of two groups of genetic variants in closely related Microcystis strains. Sequence analyses suggested that the genetic variation is due to recombination events between mcyB1 and the corresponding domains in mcyC. Each variant could be correlated to a particular microcystin isoform profile, as identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Among the Microcystis species studied, we found 11 strains containing different variants of the mcyABC gene cluster and 7 strains lacking the genes. Furthermore, there is no concordance between the phylogenies generated with mcyB1, 16S ribosomal DNA, and DNA fingerprinting. Collectively, these results suggest that recombination between imperfect repeats, gene loss, and horizontal gene transfer can explain the distribution and variation within the mcyABC operon.


Hepatocellular carcinoma complicating biliary atresia after Kasai portoenterostomy.
Kasai portoenterostomy (PE) increases the survival for children with biliary atresia (BA) and consequently postpones subsequential liver transplantation. All long-term survivors, however, develop complications of biliary cirrhosis. We report a case of hepatocellular carcinoma (HCC) in a 19-year-old male patient with BA and Kasai PE. The preoperative abdominal ultrasound and magnetic resonance imaging showed a large hepatic mass (diameter 10 cm). The serum alpha-fetoprotein level was within normal range. Pathologic findings of the mass, after orthotopic liver transplantation, demonstrated a well-differentiated HCC (T1N0M0). HCC is a rare complication of BA, but will intensively impair the survival. Therefore, clinicians should be alert to the development of HCC in this very young patient group. Repeated sequential magnetic resonance imaging of the native liver in patients with Kasai PE is necessary to monitor possible malignant transformation of liver nodules that may potentially develop as a result of chronic cholestatic liver disease.


Nizatidine, an H2-blocker. Its metabolism and disposition in man.
The disposition of a single oral dose of about 150 mg of nizatidine, an H2-blocker, was studied in five men. Plasma levels of both parent drug and radioactivity peaked in 1-3 hr. Nizatidine accounted for about 60% of the plasma radioactivity. The t1/2 of nizatidine was 1.6 hr. About 35% of nizatidine became bound to plasma proteins in vitro, particularly to alpha-1-glycoprotein. Warfarin, acetaminophen, phenobarbital, propantheline, diazepam, and propranolol did not notably affect the amount of nizatidine bound. Two to 3 times more radioactivity was in plasma than in blood cells or saliva. Greater than 90% of the dose of nizatidine was excreted in urine, probably by glomerular filtration and active tubular secretion. Nizatidine accounted for about 65% of the urinary radioactivity. The major metabolite of nizatidine was N2-monodesmethylnizatidine; it represented about 7% of the nizatidine dosage. Another metabolite, constituting about 5% of the dose, is proposed to be nizatidine N2-oxide. Nizatidine sulfoxide also may be a minor metabolite of nizatidine.


Sec5, a member of the exocyst complex, mediates Drosophila embryo cellularization.
Cellularization of the Drosophila embryo is the process by which a syncytium of approximately 6000 nuclei is subdivided into discrete cells. In order to individualize the cells, massive membrane addition needs to occur by a process that is not fully understood. The exocyst complex is required for some, but not all, forms of exocytosis and plays a role in directing vesicles to appropriate domains of the plasma membrane. Sec5 is a central component of this complex and we here report the isolation of a new allele of sec5 that has a temperature-sensitive phenotype. Using this allele, we investigated whether the exocyst complex is required for cellularization. Embryos from germline clones of the sec5(ts1) allele progress normally through cycle 13. At cellularization, however, cleavage furrows do not invaginate between nuclei and consequently cells do not form. A zygotically translated membrane protein, Neurotactin, is not inserted into the plasma membrane and instead accumulates in cytoplasmic puncta. During cellularization, Sec5 becomes concentrated at the apical end of the lateral membranes, which is likely to be the major site of membrane addition. Subsequently, Sec5 concentrates at the sub-apical complex, indicating a role for Sec5 in the polarized epithelium. Thus, the exocyst is necessary for, and is likely to direct, the polarized addition of new membrane during this form of cytokinesis.


Modes of operation and variable stoichiometry of the furosemide- sensitive Na and K fluxes in human red cells.
We report in this paper different modes of Na and K transport in human red cells, which can be inhibited by furosemide in the presence of ouabain. Experimental evidence is provided for inward and outward coupled transport of Na and K, Ki/Ko and Nai/Nao exchange, and uncoupled Na or K efflux. The outward cotransport of Na and K was defined as the furosemide-sensitive (FS) component of Na and K effluxes into choline medium and as the Cl-dependent or cis-stimulated component of the ouabain-resistant (OR) Na and K effluxes. Inward cotransport of Na and K was defined by the stimulation by external Na (Nao) of the K influx and the stimulation by external K (Ko) of the Na influx in the presence of ouabain. Both effects were FS and Cl dependent. Experimental evidence for an FS Ki/Ko exchange pathway of the Na/K cotransport was provided by (a) the stimulation by external K of FS K influx and efflux, and (b) the stimulation by internal Na or K of FS K influx in the absence of external Na. Evidence for an FS Nai/Nao exchange pathway was provided by the stimulation of FS Na influx by internal Na from a K-free medium (130 mM NaCl). This pathway was four to six times smaller than the Ki/Ko exchange. In cells containing only Na or K, incubated in media containing only Na or K, respectively, there was FS efflux of the cation without simultaneous inward transport (FS uncoupled Na and K efflux). The stoichiometric ratio of FS outward cotransport of Na and K into choline medium varied with the ratio of Nai-to-Ki concentrations, and when Nai/Ki was close to 1, the ratio of FS outward Na to K flux was also 1. In choline media, FS Na efflux was inhibited by external K (noncompetitively), whereas FS k efflux was stimulated. The stimulation of FS K efflux was due to the stimulation by Ko of the Ki/Ko exchange pathway. Thus, the stoichiometry of FS Na and K effluxes also varied in the presence of external K. A minimal model for a reaction scheme of FS Na and K transport accounts for cis stimulation, trans inhibition, and trans stimulation, and for variable stoichiometry of the FS cation fluxes.


Mortality Rates and Mortality Risk Factors in Older Adults with Dementia from Low- and Middle-Income Countries: The 10/66 Dementia Research Group Population-Based Cohort Study.
Dementia is the main cause of disability in older people living in low- and middle-income countries (LMIC). Monitoring mortality rates and mortality risk factors in people with dementia (PwD) may contribute to improving care provision. We aimed to estimate mortality rates and mortality predictors in PwD from eight LMICs. This 3-5-year prospective cohort study involved a sample of 1,488 older people with dementia from eight LMIC. Total, age- and gender-specific mortality rates per 1,000 person-years at risk, as well as the total, age- and gender-adjusted mortality rates were estimated for each country's sub-sample. Cox's regressions were used to establish the predictors of mortality. At follow-up, vital status of 1,304 individuals (87.6%) was established, of which 593 (45.5%) were deceased. Mortality rate was higher in China (65.9%) and lower in Mexico (26.9%). Mortality risk was higher in males (HR = 1.57; 95% CI: 1.32,1.87) and increased with age (HR = 1.04; 95% CI: 1.03,1.06). Neuropsychiatric symptoms (HR = 1.03; 95% CI: 1.01,1.05), cognitive decline (HR 1.04; 95% CI: 1.03,1.05), undernutrition (HR = 1.55; 95% CI: 1.19, 2.02), physical impairments (HR = 1.15; 95% CI: 1.03,1.29), and disease severity (HR = 1.43; 95% CI: 1.22,1.63) predicted higher mortality risk. Several factors predicted higher mortality risk in PwD in LMICs. Males, those with higher age, higher severity of neuropsychiatric symptoms, higher number of physical impairments, higher disease severity, lower cognitive performance, and undernutrition had higher mortality risk. Addressing these indicators of long-term adverse outcomes may potentially contribute to improved advanced care planning, reducing the burden of disease in low-resourced settings.


Contribution of dopamine D1 and D2 receptors to amygdala activity in human.
Several animal studies have demonstrated functional roles of dopamine (DA) D1 and D2 receptors in amygdala activity. However, the contribution of DA D1 and D2 receptors to amygdala response induced by affective stimuli in human is unknown. To investigate the contribution of DA receptor subtypes to amygdala reactivity in human, we conducted a multimodal in vivo neuroimaging study in which DA D1 and D2 receptor bindings in the amygdala were measured with positron emission tomography (PET), and amygdala response induced by fearful faces was assessed by functional magnetic resonance imaging (fMRI) in healthy volunteers. We used multimodality voxelwise correlation analysis between fMRI signal and DA receptor binding measured by PET. DA D1 binding in the amygdala was positively correlated with amygdala signal change in response to fearful faces, but DA D2 binding in the amygdala was not related to amygdala signal change. DA D1 receptors might play a major role in enhancing amygdala response when sensory inputs are affective.


Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome presenting as a primary calvarial lesion. Case report and review of the literature.
The synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a recently described, currently evolving clinical entity that groups together several idiopathic disorders of bone and skin formerly described under a variety of names. Among the spectrum of possible locations for the bone lesions, there is no previous report in the literature of primary involvement of the skull vault. A patient with primary involvement of the calvaria in the setting of SAPHO syndrome is described here, which, to the authors' knowledge, is the first report of such localization. The clinically and radiologically benign evolution of the different stages of the bone lesions is presented. The authors suggest that the SAPHO syndrome should be considered in the differential diagnosis of lytic, sclerotic, or hyperostotic lesions of the skull, particularly before considering invasive diagnostic procedures.


Predicting Low Accrual in the National Cancer Institute's Cooperative Group Clinical Trials.
The extent to which trial-level factors differentially influence accrual to trials has not been comprehensively studied. Our objective was to evaluate the empirical relationship and predictive properties of putative risk factors for low accrual in the National Cancer Institute's (NCI's) Cooperative Group Program, now the National Clinical Trials Network (NCTN). Data from 787 phase II/III adult NCTN-sponsored trials launched between 2000 and 2011 were used to develop a logistic regression model to predict low accrual, defined as trials that closed with or were accruing at less than 50% of target; 46 trials opened between 2012 and 2013 were used for prospective validation. Candidate predictors were identified from a literature review and expert interviews; final predictors were selected using stepwise regression. Model performance was evaluated by calibration and discrimination via the area under the curve (AUC). All statistical tests were two-sided. Eighteen percent (n = 145) of NCTN-sponsored trials closed with low accrual or were accruing at less than 50% of target three years or more after initiation. A multivariable model of twelve trial-level risk factors had good calibration and discrimination for predicting trials with low accrual (AUC in trials launched 2000-2011 = 0.739, 95% confidence interval [CI] = 0.696 to 0.783]; 2012-2013: AUC = 0.732, 95% CI = 0.547 to 0.917). Results were robust to different definitions of low accrual and predictor selection strategies. We identified multiple characteristics of NCTN-sponsored trials associated with low accrual, several of which have not been previously empirically described, and developed a prediction model that can provide a useful estimate of accrual risk based on these factors. Future work should assess the role of such prediction tools in trial design and prioritization decisions.


Pd/Brønsted acid catalysed intramolecular N-allylation of indoles and pyrroles with alkynes for the synthesis of N-fused heterocycles.
We, herein, report a Pd(0) and Brønsted acid-catalyzed redox-neutral intramolecular N-allylation of indoles and pyrroles with alkynes for the synthesis of biologically important imidazolidinone-fused N-heterocycles. The allylation is completely atom-economical and is applicable to a wide range of substrates. The methodology eliminates the use of a leaving group or an oxidizing agent, often employed for the allylation of nucleophiles. To the best of our knowledge, N-allylation of indoles and pyrroles with alkynes has not been reported to date.


"Learning on a chip:" Microfluidics for formal and informal science education.
Microfluidics is a technique for the handling of small volumes of liquids on the order of picoliters to nanoliters and has impact for miniaturized biomedical science and fundamental research. Because of its multi- and interdisciplinary nature (i.e., combining the fields of biology, chemistry, physics, and engineering), microfluidics offers much potential for educational applications, both at the university level as well as primary and secondary education. Microfluidics is also an ideal "tool" to enthuse and educate members of the general public about the interdisciplinary aspects of modern sciences, including concepts of science, technology, engineering, and mathematics subjects such as (bio)engineering, chemistry, and biomedical sciences. Here, we provide an overview of approaches that have been taken to make microfluidics accessible for formal and informal learning. We also point out future avenues and desired developments. At the extreme ends, we can distinguish between projects that teach how to build microfluidic devices vs projects that make various microscopic phenomena (e.g., low Reynolds number hydrodynamics, microbiology) accessible to learners and the general public. Microfluidics also enables educators to make experiments low-cost and scalable, and thereby widely accessible. Our goal for this review is to assist academic researchers working in the field of microfluidics and lab-on-a-chip technologies as well as educators with translating research from the laboratory into the lecture hall, teaching laboratory, or public sphere.


[Circumstances and toxicological characteristics of deadly opiates poisoning].
Facts of prehospital death of 109 heroin addicts are analysed and systematized. It is shown that examination of the corpse at the point of detection may provide information on the circumstances of death and its cause. Correlation between morphine concentration in the corpse tissues and circumstances of death is studied. It is found that information about the victim and facts of his/her death suggest cause of death and help in directions of post-mortem examination and choice of diagnostic procedures.


Systematic review and meta-analysis of case-matched studies comparing open and laparoscopic distal pancreatectomy: is it a safe procedure?
Distal pancreatectomies and enucleations have become the most popular laparoscopic pancreatic resections and in some centers outnumber the traditional open approach. The aim of this study was to systematically review the literature on the safety of laparoscopic distal pancreatectomies (LDP) in relation to open distal pancreatectomies in the management of adult patients and, where possible, perform a meta-analysis of reported outcomes. We searched MEDLINE, EMBASE, Web of knowledge, and the Cochrane Database of Systematic Reviews using the following keywords: pancreas, pancreatectomy, pancreatic, laparoscopic, laparoscopy. Publication dates and language restrictions were applied. The Newcastle Ottawa scale was used for study quality assessment. Four eligible studies were identified with a total of 665 patients. On average, LDPs had a longer operation time by 17.7 minutes (9.5%) and a reduced hospital stay by 2.7 days. Morbidity and mortality were low using both approaches. This study represents the strongest evidence (level 3a) to date that LDPs are a safe operation. However, there is still a need for randomized controlled trials to confirm this.


Factors associated with newborn care knowledge and practices in the upper Himalayas.
Globally, neonatal deaths remain a major public health challenge and account for the majority of deaths occurring among children under five years of age. Despite Nepal's significant achievements in meeting the maternal and child health targets of the Millennium Development Goals, an estimated 23,000 Nepalese children under five years die every year, with three out of five babies dying within the first 28 days of life. This study therefore aimed to examine the level of knowledge and practices of newborn care among Nepalese mothers in the upper Himalayas and the factors associated with these. A community based cross-sectional study was conducted among 302 randomly selected mothers with children under two years of age in Tripurasundari Municipality of Dolpa district, an upper Himalayan region of Nepal. Mothers were interviewed using semi-structured questionnaires. Mean score for knowledge and Bloom's criteria for practice were considered to categorize newborn care knowledge and practices. Multivariate logistic regression was used to identify factors associated with the newborn care knowledge and practices. In this study, 147 (48.7%) of the mothers were found to have inadequate knowledge of newborn care, while 102 (33.8%) mothers had reported unsatisfactory newborn care practices. Mothers with at least secondary level of formal education were more likely to possess adequate newborn care knowledge compared to mothers who never attended school (AOR 4.93 at 95% CI 1.82-13.33). Mothers whose first pregnancy occurred between the ages of 20-24 years (AOR 3.89 at 95% CI 1.81-8.37) were also more likely to possess adequate newborn care knowledge, compared to mothers with a younger age at first pregnancy. Furthermore, mothers who had completed at least four ANC visits (AOR 2.89 at 95% CI 1.04-7.96), mothers who had completed three PNC visits (AOR 2.79 at 95% CI 1.16-6.72) and mothers who reported that their nearest health facility was less than one hour (30-59 minutes) walking distance (AOR 3.66 at 95% CI 1.43-9.33) had higher odds of having adequate newborn care knowledge. Similarly, mothers whose household monthly income was more than $100 (AOR 4.17 at 95% CI 1.75-9.69), mothers who had completed three PNC visits (AOR 3.27 at 95% CI 1.16-9.20) and mothers with adequate newborn care knowledge (AOR 15.35 at 95% CI 5.82-40.47) were found to be more likely to practice a satisfactory level of newborn care practices in adjusted analysis. The study revealed high prevalence of inadequate newborn care and knowledge amongst mothers in upper Himalayan dwellings. Approximately one third of all interviewed mothers practiced suboptimal newborn care. The results indicate an urgent need to increase awareness of neonatal services available to mothers and to prioritize investments by local governments in neonatal health services, in order to improve accessibility and quality of care for mothers and newborns.


Inhibition of cellular mediated immunity in marihuana smokers.
The cellular mediated immunity of 51 young chronic marihuana smokers. as evaluated by the lyomphocyte response in vitro to allogeneic cells and to phytohemagglutinin, was significantly decreased and similar to that of patients in whom impairment of T (thymus derived) cell immunity is known to occur. This inhibition of blastogenesis might be related to an impairment of DNA synthesis.