[An autopsy case of amyotrophic lateral sclerosis with ampulla cardiomyopathy].
We herein report an autopsy case of a 63-year-old man with amyotrophic lateral sclerosis (ALS) who developed "ampulla cardiomyopathy." At the age of 56, he noticed a progressive weakness in his right upper extremity. One year later, a progressive weakness of the left upper extremity began. Dropped head and progressive weakness of the lower extremities emerged at the ages of 61 and 62, respectively. Intravenous immunoglobulin and plasma-exchange therapies did not improve his weakness. At the age of 63, one month before his death, he was hospitalized due to aspiration pneumonia. A tracheostomy was performed to secure his airway. Four days after the operation, an ST elevation of his electrocardiogram was incidentally found on the ECG monitor. An echocardiogram revealed diffuse hypokinesia of the wall of the left ventricle except in the basal portion, which is the typical finding of "ampulla cardiomyopathy." Wall motion of the left ventricle improved and his circulatory condition was stabilized after treatment, but his condition thereafter worsened again and he died 3 weeks later. An autopsy examination revealed diffuse fibrosis and degeneration of the cardiomyofibers. Neuropathological examination revealed neuronal cell loss, Bunina bodies and skein-like inclusions in the hippoglossal nuclei. In the thoracic spinal cord, degenarated anterior horn cells were seen and macrophage permeation in the corticospinal tract were shown by CD68 immunostaining. Therefore, the final neuropathological diagnosis was ALS. This report is the first autopsy case of ALS complicated with "ampulla cardiomyopathy."


Relaxant effect of xenin on rat ileum is mediated by apamin-sensitive neurotensin-type receptors.
The action of xenin, a novel 25-residue peptide of the neurotensin (NT)/xenopsin family, was investigated in isolated rat ileal muscle strips and in dispersed longitudinal smooth muscle cells of rat small intestine in vitro. Xenin relaxes KCl-precontracted ileal strips dose dependently (1 nM-3 microM). The order of potency of the investigated peptides was as follows: xenopsin = NT = xenin > neuromedin N. Kinetensin was inactive. Tetrodotoxin, hexamethonium, tetraethylammonium, 4-aminopyridine, and NG-nitro-L-arginine did not influence the relaxant effects of xenin or NT, whereas the K+ channel blocker apamin nearly abolished their effects. Desensitization against one of the peptides or blockade of NT receptors by SR-48692 prevented the effect of xenin and NT. Structure-activity experiments revealed that the COOH-terminal part of the molecules of xenin and NT is essential for biological activity. Experiments with isolated dispersed smooth muscle cells and binding studies on intestinal smooth muscle cell membranes confirmed and extended the results obtained with muscle strips. In conclusion, xenin relaxes rat ileal smooth muscle via a muscular NT-type apamin-sensitive receptor.


Antigenic stimulation in T-cell cultures in cardiomyopathies: differences in cytokine profiles.
Immune-mediated mechanisms are involved in the pathogenesis of cardiomyopathies. In this study, we investigate which pattern of immune response (Th1 or Th2) lies behind these diseases by analysing the basic cytokines secreted from PHA-cultured T lymphocytes and determining what differences, if any, exist between dilated cardiomyopathy (DMC) and hypertrophic cardiomyopathy (HCM). Two groups of patients were studied: 10 patients with DCM and 10 patients with HCM. Age- and sex-matched healthy individuals were used as controls. PHA-cultured T lymphocytes in the presence or absence of different myocardial antigen (MA) concentrations were measured. Interleukine-2 (IL-2), Interleukine-6 (IL-6) and Interferon-gamma (IFN-gamma) levels were measured in culture supernatants by an ELISA method. At the same time, delayed-type hyperactivity (DTH) against the same antigenic preparation was measured by the leukocyte migration inhibitory index technique. Patients were subdivided into DTH-positive and DTH-negative and re-examined for IL-2 cytokine expression. IL-6 levels were found to increase both in the presence and in the absence of MA in the patient groups compared to the controls. IL-2 levels were decreased in both groups, in an antigen dose-related manner. Anergic patients showed a further reduction in IL-2 levels for both groups of patients. IFN-gamma remained unaffected in the patient groups. Almost half of the patients exhibited anergy to the DTH reaction against MA. We conclude that, upon antigenic stimulation, the initially mounted immune response (increased IL-6) is somehow blocked/switched off in patients, resulting in an immunologic tolerance/unresponsiveness to MA (IL-2 decreased, IFN-gamma unchanged). Finally, increased IL-6 could lead to a perpetuation of immunologic injury through the release of oxygen-free radicals with a cytotoxic effect on the myocardium. We hypothesize an antigen-related, defective macrophage-Th1 cell reaction, which accounts for the differences in the IL-2 profile between the DCM and HCM groups, that might cause local immune responses to lead to immunosuppression (immune tolerance effect), thus contributing to the pathogenesis of cardiomyopathies.


[Respiratory depression following medication change from tramadol to morphine].
Respiratory depression following change of medication from tramadol to morphine is described in two patients. Tramadol is metabolized by cytochromoxidase CYP2D6 to O-desmethyl-tramadol with opioid agonist activity. Of the western population 7% have a mutation of the gene responsible for CYP2D6, resulting in low enzyme activity. These persons will have little effect of tramadol. When tailoring analgesia, the lack of response to tramadol may be interpreted as a need for opioid dose increase. In such cases, excessive opioid doses may be prescribed resulting in opioid side effects.


Emergency portosystemic shunt in patients with variceal bleeding.
Thirty-five patients for whom emergency sclerotherapy or conservative treatment, or both, failed to arrest variceal bleeding, or who had early rebleeding and required emergency portosystemic shunts (EPSS) were studied. EPSS permanently controlled the variceal bleeding in all but one patient. In this patient, the shunt was patent as demonstrated by angiography. Esophageal varices disappeared in 18 patients and were reduced in 14. Three patients died before the endoscopic examination could be performed. The causes of death were hepatic failure in two and bleeding ulcerations of the gastric fundus in the other patient. One patient was classified in Child's category B and two in Child's category C. Thirty-two patients submitted to EPSS and were discharged alive. Twelve of these patients subsequently died, at an average of 11.2 months after undergoing the shunt procedure. Four of 12 patients died of hepatic failure; two patients died of hepatomas; two, other neoplasia; three, hemorrhaging duodenal ulcers, and one patient, renal failure. Analysis of actuarial survival rates showed that the five year survival rate was 43 per cent. The long term survival rates were fewer for patients with Child's category C than for those with combined Child's categories A and B (five year survival rates were 21 versus 55 per cent; p less than 0.05). During the follow-up period, none of the patients had variceal bleeding. Chronic encephalopathy developed in six, which was mild in three, moderate in one instance and severe in two. It developed soon after EPSS, with onset in the first month after discharge in three. Thus, when conservative treatment fails to arrest variceal bleeding, EPSS should be performed to guarantee definitive control of hemorrhage and prolong the survival period.


Trauma experience comparison of army forward surgical team surgeons at Ben Taub Hospital and Madigan Army Medical Center(2)(2).
Far forward life-saving surgical care is the mission of an army forward surgical team (FST). Trauma skill maintenance is necessary to complete that mission. A new program has been developed for FST training using the resources of a Level 1 trauma center. We sought to compare the experience of FST surgeons at a major urban trauma center with the yearly trauma experience at an army Level 2 trauma center.General surgeons of the 250th FST prospectively tabulated data for trauma patients during a September 1999 unit deployment to Ben Taub Hospital (Houston, Texas). Data collected included nature and location of injury, hospital admission, and surgical intervention. During 1999, similar data were collected at Madigan Army Medical Center (MAMC) (Ft. Lewis, Washington), home station of the 250th and Level 2 trauma center since November 1998.The FST general surgeons observed 319 injuries. Of those injured, 104 were admitted and 19 underwent urgent operation. Direct participation by FST general surgeons in the operative procedures varied. In 1999, MAMC general surgeons treated 455 trauma victims in direct supervision of Army general surgery residents. Madigan Army Medical Center general surgeons admitted 304 and urgently operated on 57 trauma patients, while 107 patients were transferred to another institution for definitive management of orthopedic and nonoperative neurosurgical injuries.CONCLUSIONS:The volume of trauma surgical cases at MAMC during 1999 was 3 times that seen in the 1-month rotation at Ben Taub. General surgeons performed more trauma and abdominal surgery at MAMC with significantly more direct involvement in patient care and operative procedures. The experience of the 250th FST does not justify trauma sustainment deployments for surgeons from military trauma centers.


On the relationship between upper-body strength, power, and sprint performance in ice sledge hockey.
Ice sledge hockey is a popular paralympic team sport where players rely entirely on their upper body to propel themselves rapidly across the ice surface. The isolated and repetitive poling movements provide a good model for examining upper-body sprint ability and the related movement and strength characteristics. Therefore, the purpose of the present study was to investigate the relationship between upper-body maximal strength, power, and sprint performance in ice sledge hockey. Thirteen male ice sledge hockey players from the Norwegian national team performed three 30-m maximal sprint tests recorded by fixed light sensors. The best 30-m time for each subject was used for further analyses, and the sprint was analyzed more in detail for the first and last 10-m split times and kinematics (cycle length and rate) using photocells and 2-dimensional video analysis. One repetition maximum (1RM) strength and peak power were assessed in the bench press, bench pull, and pull-down exercises using a barbell and a linear encoder. Both 1RM strength and peak power for all the 3 strength exercises correlated significantly with the total sprint time (-0.75 < r < - 0.86, all p < 0.005), the first (0.60 < r < 0.72, all p < 0.05), and the last (0.74 < r < 0.83, all p < 0.05) 10-m split times in the 30-m sprint test. There were no significant relationships between sprint kinematics and 1RM strength and peak power. Overall, these results demonstrate that there are close relationships between upper-body strength, power, and sprint performance in highly trained athletes and that the ability to produce propulsion and high frequency in combination is important for the sprint abilities in ice sledge hockey.


On-chip manipulation of single photons from a diamond defect.
Operating reconfigurable quantum circuits with single photon sources is a key goal of photonic quantum information science and technology. We use an integrated waveguide device containing directional couplers and a reconfigurable thermal phase controller to manipulate single photons emitted from a chromium related color center in diamond. Observation of both a wavelike interference pattern and particlelike sub-Poissionian autocorrelation functions demonstrates coherent manipulation of single photons emitted from the chromium related center and verifies wave particle duality.


Psychological effects of implantable cardioverter defibrillator shocks. A review of study methods.
The implantable cardioverter defibrillator (ICD) saves lives but clinical experience suggests that it may have detrimental effects on mental health. The ICD shock has been largely blamed as the main offender but empirical evidence is not consistent, perhaps because of methodological differences across studies. To appraise methodologies of studies that assessed the psychological effects of ICD shock and explore associations between methods and results. A comprehensive search of English articles that were published between 1980 and 30 June 2013 was applied to the following electronic databases: PubMed, EMBASE, NHS HTA database, PsycINFO, Sciencedirect and CINAHL. Only studies testing the effects of ICD shock on psychological and quality of life outcomes were included. Data were extracted according to a PICOS pre-defined sheet including methods and study quality indicators. Fifty-four observational studies and six randomized controlled trials met the inclusion criteria. Multiple differences in methods that were used to test the psychological effects of ICD shock were found across them. No significant association with results was observed. Methodological heterogeneity of study methods is too wide and limits any quantitative attempt to account for the mixed findings. Well-built and standardized research is urgently needed.


Contribution and regulation of TRPC channels in store-operated Ca2+ entry.
Store-operated calcium entry (SOCE) is activated in response to depletion of the endoplasmic reticulum-Ca(2+) stores following stimulation of plasma membrane receptors that couple to PIP2 hydrolysis and IP3 generation. Search for the molecular components of SOCE channels led to the identification of mammalian transient receptor potential canonical (TRPC) family of calcium-permeable channels (TRPC1-TRPC7), which are all activated in response to stimuli that result in PIP2 hydrolysis. While several TRPCs, including TRPC1, TRPC3, and TRPC4, have been implicated in SOCE, the data are most consistent for TRPC1. Extensive studies in cell lines and knockout mouse models have established the contribution of TRPC1 to SOCE. Furthermore, there is a critical functional interaction between TRPC1 and the key components of SOCE, STIM1, and Orai1, which determines the activation of TRPC1. Orai1-mediated Ca(2+) entry is required for recruitment of TRPC1 and its insertion into surface membranes while STIM1 gates the channel. Notably, TRPC1 and Orai1 generate distinct patterns of Ca(2+) signals in cells that are decoded for the regulation of specific cellular functions. Thus, SOCE appears to be a complex process that depends on temporal and spatial coordination of several distinct steps mediated by proteins in different cellular compartments. Emerging data suggest that, in many cell types, the net Ca(2+) entry measured in response to store depletion is the result of the coordinated regulation of different calcium-permeable ion channels. Orai1 and STIM1 are central players in this process, and by mediating recruitment or activation of other Ca(2+) channels, Orai1-CRAC function can elicit rapid changes in global and local [Ca(2+)]i signals in cells. It is most likely that the type of channels and the [Ca(2+)]i signature that are generated by this process reflect the physiological function of the cell that is regulated by Ca(2+).


Home management of mild to moderately severe community-acquired pneumonia: a randomised controlled trial.
To determine whether community management of mild to moderate community-acquired pneumonia (CAP) is as effective and acceptable as standard hospital management of CAP. Randomised controlled trial. Christchurch, New Zealand, primary and secondary care. 55 patients presenting or referred to the emergency department at Christchurch Hospital with mild to moderately severe pneumonia, assessed using a validated pneumonia severity assessment score, from July 2002 to October 2003. Hospital treatment as usual or comprehensive care in the home delivered by primary care teams. Primary: days to discharge, days on intravenous (IV) antibiotics, patient-rated symptom scores. Secondary: health status measured using level of functioning at 2 and 6 weeks, patient satisfaction. The median number of days to discharge was higher in the home care group (4 days; range, 1-14) than in the hospital groups (2 days; range, 0-10; P = 0.004). There was no difference in the number of days on IV antibiotics or on subsequent oral antibiotics. Patient-rated symptom scores at 2 and 6 weeks, median change in symptom severity from baseline to 6 weeks, and general functioning at 2 and 6 weeks did not differ between the groups. Patients in both groups were satisfied with their treatment, with a clear preference for community treatment (P < 0.001). Mild to moderately severe CAP can be managed effectively in the community by primary care teams. This model of comprehensive care at home can be implemented by primary care teams with suitable funding structures.


[Radiation therapy in breast carcinoma].
Strategies in treating breast cancer have been changed in the last years. In Stage I and early II radical operation techniques have been used not more. Today conservative methods are preferred in combination with axillary lymphonodectomy. This implies necessity of postoperative irradiation. Longterm results are not different between breast preserving methods and radical mastectomy. Cosmetic results can be excellent following high doses of radiation. Side effects are minimal and of non important clinical value. If there is a local recurrence or a second primary tumor, a secondary mastectomy can solve the problem in many cases.


Assisted Fontan procedure: animal and in vitro models and computational fluid dynamics study.
Fontan connection with intermittent compression by wrapped latissimus dorsi (LD) was tested in vivo, in vitro and by means of computational fluid dynamics (CFD). Experimental study: LD was conditioned in four pigs for three weeks before Fontan connection by valved conduit wrapped with LD. Mock circuit: Inflatable cuff wrapped around valved conduit provided intermittent external compression, with pressure and flow measured at driving pressure of 8 or 16 mmHg. CFD study: A circuit was tested for possible increase above basal flow (4 l/min) with intermittent external compression. Experimental study: Intermittent conduit compression by LD provided mean 7% decrease of baseline PA pressure, with simultaneous flow increase of 2%. Mock circuit: By raising the driving pressure from 8 to 16 mmHg, the flow increased with baseline PVR (56%) and with elevated PVR (80%). Total pulmonary flow was reduced during intermittent external compression with both baseline and elevated PVR. CFD study: Compression with 13.0 mmHg provided 4.9% increase of total pulmonary flow with substantial increase of the peak flow (92%). In vivo and in vitro, the increased flow produced by compressing a conduit was confounded by the inevitable intermittent flow restriction. Mathematical model using lower pressure for intermittent external compression showed potential for increase in pulmonary flow.


Selective amplification of mouse mammary tumor virus in mammary tumors of GR mice.
DNAs extracted from the mammary tumors of GR mice were analyzed for mouse mammary tumor virus proviral sequences by the restriction enzyme-Southern blot procedure. The tumor DNAs contain more proviral copies of mouse mammary tumor virus than DNA from a nonmalignant tissue. The degree of proviral amplification is small (ca. one to five additional copies) and appears to be variable from tumor to tumor. The restriction patterns of the amplified proviral sequences suggest a clonal origin for the tumor mass. In addition, the restriction patterns observed after digestion with the enzymes BglII and SacI indicate that only one of the proviruses endogenous to GR mice is amplified. The amplified provirus found in GR mammary tumors is identical to the provirus that is missing in GR-Mtv-2- mice, a congenic line exhibiting a low mammary tumor incidence.


An R package implementation of multifactor dimensionality reduction.
A breadth of high-dimensional data is now available with unprecedented numbers of genetic markers and data-mining approaches to variable selection are increasingly being utilized to uncover associations, including potential gene-gene and gene-environment interactions. One of the most commonly used data-mining methods for case-control data is Multifactor Dimensionality Reduction (MDR), which has displayed success in both simulations and real data applications. Additional software applications in alternative programming languages can improve the availability and usefulness of the method for a broader range of users. We introduce a package for the R statistical language to implement the Multifactor Dimensionality Reduction (MDR) method for nonparametric variable selection of interactions. This package is designed to provide an alternative implementation for R users, with great flexibility and utility for both data analysis and research. The 'MDR' package is freely available online at http://www.r-project.org/. We also provide data examples to illustrate the use and functionality of the package. MDR is a frequently-used data-mining method to identify potential gene-gene interactions, and alternative implementations will further increase this usage. We introduce a flexible software package for R users.


Current initial therapy of stage III and IV ovarian cancer: challenges for managed care.
Patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III or stage IV) have improved their long-term prognosis, but the majority will still die of their disease. The current standard therapy, which involves aggressive cytoreductive surgery (removal of all visible tumor) followed by platinum/paclitaxel chemotherapy, has increased 5-year survival rates considerably over the last three decades. The choice of treatment for patients with stage III or IV disease in the managed care setting must consider survival rates, patient quality of life, and cost-effectiveness. Two chemotherapy combinations, cisplatin/paclitaxel and carboplatin/paclitaxel, appear comparable in efficacy in advanced disease, but are currently being investigated in clinical trials to compare side effects, quality-of-life parameters, and cost-effectiveness. The results of these trials may determine which chemotherapy combination becomes the standard of care for first-line treatment. Managed care organizations and patients can also benefit from a multidisciplinary approach to cancer care that includes additional support, such as risk assessment programs, the use of specialists (gynecologic oncologists), and psychosocial counseling. As the search for more effective agents and other therapeutic modalities continues, the focus of future research may be to find specific biomarkers of ovarian cancer, which will help detect disease at its earliest stages.


HRCT features of acute rejection in patients with bilateral lung transplantation: the usefulness of lesion distribution.
This study sought to evaluate the high-resolution computed tomography (HRCT) features of acute rejection and to assess the diagnostic accuracy of HRCT for acute rejection considering distribution of lesions in patients with bilateral lung transplantation (BLT). Between March 2010 and June 2012, 48 transbronchial lung biopsies (TBLBs) and HRCT were performed simultaneously in 26 patients who underwent BLT. We evaluated the presence of ground glass opacity (GGO), consolidation, nodule, bronchial wall thickening, interlobular septal thickening, pleural effusion, atelectasis, bronchiectasis, and cardiomegaly on the HRCT images. The distribution of lesions was analyzed according to bilaterality or upper/lower predominance. Acute rejection was determined on the basis of the pathologic results of TBLB. We evaluated potential correlations of HRCT features with acute rejection, then assessed overall diagnostic accuracy of various HRCT features in combination to diagnose acute rejection in the transplanted lung. Among the 48 TBLBs, 8 were diagnosed as acute rejection (A1, 4 cases; A2, 2 cases; and A3, 2 cases) pathologically. Two A1 rejections and one A2 rejection appeared normal on computed tomography images. Without considering the distribution of lesions, interlobular septal thickening was significantly associated with acute rejection (P = .010) only. Regarding the distribution of lesions on HRCT images, not only interlobular septal thickening but also GGO was significantly associated with acute rejection (P < .05). The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of the HRCT scan in the evaluation of acute rejection were 50%, 97.5%, 80%, 90.1%, and 89.6%, when the bilateral GGO and interlobular septal thickening with lower predominance were considered as the positive finding. HRCT findings considering lesion distribution could be a useful tool in diagnosing acute rejection in patients with BLT.


Nickel-manganese sulfido carbonyl cluster complexes. synthesis, structure, and properties of the unusual paramagnetic complexes Cp2Ni2Mn(CO)3(mu 3-E)2, E = S, Se.
The reaction of Mn(2)(CO)(7)(mu-S(2)) with [CpNi(CO)](2) yielded the paramagnetic new compound Cp(2)Ni(2)Mn(CO)(3)(mu(3)-S)(2) (1) and a new hexanuclear metal product Cp(2)Ni(2)Mn(4)(CO)(14)(mu(6)-S(2))(mu(3)-S)(2) (2). Structurally, compound 1 contains two triply bridging sulfido ligands on opposite sides of an open Ni(2)Mn triangular cluster. EPR and temperature-dependent magnetic susceptibility measurements of 1 show that it contains one unpaired electron. The electronic structure of 1 was determined by Fenske-Hall molecular orbital calculations which show that the unpaired electron occupies a low lying antibonding orbital delocalized unequally across the three metal atoms. The selenium homologue Cp(2)Ni(2)Mn(CO)(3)(mu(3)-Se)(2) (3) was obtained from the reaction of a mixture of Mn(2)(CO)(10) and [CpNi(CO)](2) with elemental selenium and Me(3)NO.2H(2)O. It also has one unpaired electron. Compound 1 reacted with elemental sulfur to yield the dinickeldimanganese compound, Cp(2)Ni(2)Mn(2)(CO)(6)(mu(4)-S(2))(mu(4)-S(5)), 4, which can also be made from the reaction of Mn(2)(CO)(7)(mu-S(2)) with [CpNi(CO)](2) and sulfur. Compound 4 was converted back to 1 by sulfur abstraction using PPh(3). The reaction of Mn(2)(CO)(10) with [CpNi(CO)](2) in the presence of thiirane yielded the ethanedithiolato compound CpNiMn(CO)(3)(mu-SCH(2)CH(2)S) (5), which was also obtained from the reaction of Mn(4)(CO)(15)(mu(3)-S(2))(mu(4)-S(2)) with [CpNi(CO)](2) in the presence of thiirane. Compound 5 reacted with additional quantities of thiirane to yield the new compound CpNiMn(CO)(3)[mu-S(CH(2)CH(2)S)(2)], 6, which contains a 3-thiapentanedithiolato ligand that bridges the two metal atoms. Compound 6 was also obtained from the reaction of Mn(2)(CO)(10) with [CpNi(CO)](2) and thiirane. The molecular structures of the new compounds 1-6 were established by single-crystal X-ray diffraction analyses.


Prevalence and risk factors for SARS-CoV-2 infection in children with and without symptoms seeking care in Managua, Nicaragua: results of a cross-sectional survey.
This study aimed to capture key epidemiological data on SARS-CoV-2 infection in Nicaraguan children (≤18 years) seeking medical care, between 6 October and 16 November 2020. In this cross-sectional study, 418 children were recruited: 319 with symptoms characteristic of COVID-19 and 99 with no symptoms of illness. Children were tested for SARS-CoV-2 RNA using loop-mediated isothermal amplification. A questionnaire was employed to identify symptoms, risk factors, comorbidities and COVID-19 prevention measures. Research was carried out in four hospitals and two clinics in Managua, Nicaragua, where schools and businesses remained open throughout the COVID-19 pandemic. Children were enrolled into a possible COVID-19 group if presenting with clinical symptoms. A comparison group included children lacking any COVID-19 symptoms attending routine check-ups or seeking care for issues unrelated to COVID-19. A high prevalence (43%) of SARS-CoV-2 infection was found, which was relatively equivalent in symptomatic and non-symptomatic children. Age distribution was similar between symptomatic and non-symptomatic children testing positive for SARS-CoV-2. Symptomatic children who tested positive for SARS-CoV-2 were 2.7 times more likely to have diarrhoea (26.7% in positive vs 12.0% in negative; OR=2.7 (95% CI 1.5 to 4.8), p=0.001) and were 2.0 times more likely to have myalgia (17.8% in positive vs 9.8% in negative; OR=2.0 (95% CI 1.0 to 3.8), p=0.04). Children with COVID-19 symptoms, who tested positive for SARS-CoV-2, were more likely to be under age 5 years and to have a pre-existing comorbid condition than children who tested positive but did not have symptoms. This is the first paediatric study to provide laboratory-confirmed data on SARS-CoV-2 infection in Nicaragua, crucial for paediatric health services planning and a successful COVID-19 response. The high prevalence of the virus suggests widespread and sustained community transmission, underscoring the urgent need for robust data on the true extent of SARS-CoV-2 infection throughout Nicaragua.


Selective chemical inhibition of agr quorum sensing in Staphylococcus aureus promotes host defense with minimal impact on resistance.
Bacterial signaling systems are prime drug targets for combating the global health threat of antibiotic resistant bacterial infections including those caused by Staphylococcus aureus. S. aureus is the primary cause of acute bacterial skin and soft tissue infections (SSTIs) and the quorum sensing operon agr is causally associated with these. Whether efficacious chemical inhibitors of agr signaling can be developed that promote host defense against SSTIs while sparing the normal microbiota of the skin is unknown. In a high throughput screen, we identified a small molecule inhibitor (SMI), savirin (S. aureus virulence inhibitor) that disrupted agr-mediated quorum sensing in this pathogen but not in the important skin commensal Staphylococcus epidermidis. Mechanistic studies employing electrophoretic mobility shift assays and a novel AgrA activation reporter strain revealed the transcriptional regulator AgrA as the target of inhibition within the pathogen, preventing virulence gene upregulation. Consistent with its minimal impact on exponential phase growth, including skin microbiota members, savirin did not provoke stress responses or membrane dysfunction induced by conventional antibiotics as determined by transcriptional profiling and membrane potential and integrity studies. Importantly, savirin was efficacious in two murine skin infection models, abating tissue injury and selectively promoting clearance of agr+ but not Δagr bacteria when administered at the time of infection or delayed until maximal abscess development. The mechanism of enhanced host defense involved in part enhanced intracellular killing of agr+ but not Δagr in macrophages and by low pH. Notably, resistance or tolerance to savirin inhibition of agr was not observed after multiple passages either in vivo or in vitro where under the same conditions resistance to growth inhibition was induced after passage with conventional antibiotics. Therefore, chemical inhibitors can selectively target AgrA in S. aureus to promote host defense while sparing agr signaling in S. epidermidis and limiting resistance development.


A systematic review of simulation for multidisciplinary team training in operating rooms.
Current simulation training initiatives predominantly occur in uniprofessional silos and do little to integrate different disciplines working in the operating room (OR). The objective of this review was to determine the current status of work describing simulation for full OR multidisciplinary teams including barriers to conducting OR multidisciplinary team training and factors contributing to successful courses. We found a total of 18 articles from 10 research groups. Various scenarios and simulators were used, and training sessions were generally perceived as realistic and beneficial by participants despite rudimentary integration of surgical and anesthetic models. Measures of performance involved a variety of both technical and nontechnical ratings of the simulations. Challenges to conducting the simulations included recruitment, model realism, and financial costs. Future work should focus on how best to overcome the barriers to implementation of team training interventions for full OR teams, particularly on how to engage senior staff to aid recruitment.


Comparative Transcriptomics and Metabolomics Analyses of Avicennia marina and Kandelia obovata under Chilling Stress during Seedling Stage.
One of the most productive ecosystems in the world, mangroves are susceptible to cold stress. However, there is currently insufficient knowledge of the adaptation mechanisms of mangrove plants in response to chilling stress. This study conducted a comparative analysis of transcriptomics and metabolomics to investigate the adaptive responses of Kandelia obovata (chilling-tolerant) and Avicennia marina (chilling-sensitive) to 5 °C. The transcriptomics results revealed that differentially expressed genes (DEGs) were mostly enriched in signal transduction, photosynthesis-related pathways, and phenylpropanoid biosynthesis. The expression pattern of genes involved in photosynthesis-related pathways in A. marina presented a downregulation of most DEGs, which correlated with the decrease in total chlorophyll content. In the susceptible A. marina, all DEGs encoding mitogen-activated protein kinase were upregulated. Phenylpropanoid-related genes were observed to be highly induced in K. obovata. Additionally, several metabolites, such as 4-aminobutyric acid, exhibited higher levels in K. obovata than in A. marina, suggesting that chilling-tolerant varieties regulated more metabolites in response to chilling. The investigation defined the inherent distinctions between K. obovata and A. marina in terms of signal transduction gene expression, as well as phenylpropanoid and flavonoid biosynthesis, during exposure to low temperatures.


Age, Sex, Body Mass Index, Education, and Social Support Influence Functional Results After Total Knee Arthroplasty.
Total knee arthroplasty (TKA) is an effective treatment for knee osteoarthritis. Patient-reported outcome after TKA is influenced by multiple patient-related factors. The aim of this study was to prospectively evaluate preoperative patient-related factors and to compare the self-reported outcomes 1 year after TKA among groups differing by age, sex, body mass index (BMI), education, and social support level. 314 patients, who underwent TKA in Vilnius Republican University Hospital between the end of 2012 and the middle of 2014, were included in a study. The preoperative and 12-month follow-up measurements were obtained using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Short Form-12 (SF-12). Differences between patient groups according to gender, age, BMI, level of education, and level of social support were analyzed. At 12-month follow-up men demonstrated better results than women in WOMAC (P = .003) and SF-12 both domains (P < .05). Patients with a higher social support demonstrated higher scores in physical function according to SF-12 (P = .008). Better preoperative WOMAC and SF-12 scores were a predictor of better outcome 1 year after surgery. There was no difference in postoperative scores in different age, BMI, and education groups according to WOMAC and SF-12. There is no difference in self-reported functional outcome between patient groups differing in age, BMI, and education. Men and socially supported patients demonstrate better postoperative functional results 12 months after TKA. Better preoperative knee function and overall physical and mental function are predictors of better outcome 1 year after TKA. Age and obesity should not be limiting factors when considering who should receive this surgery.


Introduction to the special issue on prosociality in adult development and aging: Advancing theory within a multilevel framework.
Prosociality refers to a broad set of behavioral, motivational, cognitive, affective, and social processes that contribute to, and/or are focused on, the welfare of others. This overview summarizes 10 articles included in the special issue on this topic. In discussing this research relative to existing theories, we situate this work within Penner et al.'s (Annual Review of Psychology, 56, 2005, 365-392) multilevel framework that recognizes distinct yet integrated levels of analysis to characterize micro- (i.e., intraindividual), meso- (i.e., interpersonal), and macro- (i.e., sociocultural and organizational contexts) level effects. While there is some evidence for lifespan continuity in prosocial dispositions at the micro level, the influences of long-term learning and socialization processes at the meso and macro levels are likely to be maximized in older age. Aside from formal voluteering, the adult lifespan development of prosociality has only recently received attention, especially with respect to influences beyond the micro level. This special issue encompasses research examining developmental change and stability in prosociality that collectively cuts across levels of analysis to inform theories in both adult development and aging and prosociality more generally. We propose future directions that take an integrative approach to understanding the development of prosociality by considering interactions among micro, meso, and macro levels. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells.
A study with DNA microarrays was performed to investigate the effects of two diarrhetic and one azaspiracid shellfish poison, okadaic acid (OA), dinophysistoxin-1 (DTX-1) and azaspiracid-1 (AZA-1) respectively, on the whole-genome mRNA expression of undifferentiated intestinal Caco-2 cells. Previously, the most responding genes were used to develop a dedicated array tube test to screen shellfish samples on the presence of these toxins. In the present study the whole genome mRNA expression was analyzed in order to reveal modes of action and obtain hints on potential biomarkers suitable to be used in alternative bioassays. Effects on key genes in the most affected pathways and processes were confirmed by qPCR. OA and DTX-1 induced almost identical effects on mRNA expression, which strongly indicates that OA and DTX-1induce similar toxic effects. Biological interpretation of the microarray data indicates that both compounds induce hypoxia related pathways/processes, the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress. The gene expression profile of AZA-1 is different and shows increased mRNA expression of genes involved in cholesterol synthesis and glycolysis, suggesting a different mode of action for this toxin. Future studies should reveal whether identified pathways provide suitable biomarkers for rapid detection of DSPs in shellfish.


[The cardiac and neurological manifestations of Lyme borreliosis in congenital first-degree AV block].
A 19-year-old youth was hospitalised because of sudden onset of incomplete lid closure and drooping mouth on the left. He regularly walked through fields and woods; three weeks before admission he had noted swelling and reddening on his neck, which he thought was due to an insect bite. When 9 years old a functional heart murmur and 1 degree AV block (P-R interval 0.25s) had been found. Physical examination showed peripheral facial paresis and a 2/6 systolic murmur over the aortic area. As Borreliosis (Lyme disease) was suspected, relevant laboratory tests were performed. These revealed specific IgM antibodies against Borrelia burgdorferi. Polymerase chain reaction demonstrated B. burgdorferi-specific DNA in cerebrospinal fluid and urine. The ECG showed 1 degree AV block (P-R interval 0.28s). Ceftriaxone was administered at once (4 g, followed by 2 g daily intravenously for 14 days). The P-R interval increased to maximally 0.31 s and transient incomplete right bundle branch block developed on the second day. Long-term ECG monitoring also revealed ventricular arrhythmias (Lown IVb), but they gradually disappeared. The neurological signs regressed completely within five days of the start of treatment, while the P-R interval had returned to its initial value of 0.25 s 3 months later. The case makes clear that an ECG should be recorded in borreliosis even in the absence of cardiac symptoms. Hospitalisation with long-term monitoring becomes necessary if it is abnormal.


[Educative effect of feedback after medical interview in objective structured clinical examination].
Objective Structured Clinical Examination (OSCE) is widely used to assess the core competency of dental residents. However, the educative effect of feedback in OSCE has not been fully examined. Therefore, we investigated the educative effect of formative feedback in a medical interview station. The subjects were 51 residents in the clinical training course of our dental hospital. After completing the medical interview station, residents were individually given formative feedback by evaluators and standardized patients. Two months later, residents were asked to fill in a questionnaire about the contents of feedback and self-rating mental strain level during OSCE. Videotaped performance and feedback were reviewed by investigators to check the answers to the questionnaire. Evaluators provided an average of 3.1 feedback items, and standardized patients provided an average of 1.6 feedback items for each resident. However, each resident remembered an average of 1.3 feedback items from evaluators and 0.9 from standardized patients. The lower the score of residents in the medical interview station, the more feedback items were given to residents. A significant negative correlation was found between the score of evaluators and self-rating mental strain level (Spearman rho = -0.326, p = 0.019). For effective feedback, evaluators or standardized patients should focus on 2 to 3 items of essential points in OSCE. Repetition of feedback using videotaped performance may be useful to improve communication skills for medical interview.


Understanding the uptake of a national retinopathy screening programme: An audit of patients with diabetes in two large primary care centres.
Background: Diabetic retinopathy (DR) affects 8.2% of the Irish population with type 2 diabetes over 50 years and is one of the leading causes of blindness among working-age adults. Regular diabetic retinopathy screening (DRS) can reduce the risk of sight loss. In 2013, the new national screening programme (RetinaScreen) was introduced in Ireland. Maximising DRS uptake (consent to participate in the programme and attendance once invited) is a priority, therefore it is important to identify characteristics which determine DRS uptake among those with diabetes in Ireland. We report uptake in an Irish primary care population during the initial phase of implementation of RetinaScreen and investigate factors which predict consenting to participate in the programme. Methods: In two primary care practices, data were extracted from records of people with diabetes (type 1 and type 2) aged ≥18 years who were eligible to participate in RetinaScreen between November 2013 and August 2015. Records were checked for a RetinaScreen letter. RetinaScreen were contacted to establish the status of those without a letter on file. Multivariable Poisson regression was used to examine associations between socio-demographic variables and consenting. Adjusted incident rate ratios (IRR) with 95% CI were generated as a measure of association. Results: Of 722 people with diabetes, one fifth (n=141) were not registered with RetinaScreen. Of 582 who were registered, 63% (n=365) had participated in screening. Most people who consented subsequently attended (n=365/382, 96%). People who had attended another retinopathy screening service were less likely to consent (IRR 0.65 [95%CI 0.5-0.8]; p<0.001). Other predictors were not significantly associated with consent. Conclusions: Over one third of people eligible to participate in RetinaScreen had not consented. Research is needed to understand barriers and enablers of DRS uptake in the Irish context. Implementing strategies to improve DRS uptake (consent and attendance) should be a priority.


The influence of copper and zinc on the occurrence of ischemic heart disease.
The zinc/copper hypothesis, which invokes relative or absolute deficiency of copper in the etiology of ischemic heart disease, was described. The belief that calcium (and, perhaps, magnesium) is a substance in hard water which protects against ischemic heart disease by altering copper and zinc metabolism was presented. The amounts of copper and zinc in drinking water usually are too small to produce important increases in the amounts of these elements in diets. Occasionally tap water high in copper may be an important supplement to a diet low in copper.


Beta-catenin activates a coordinated expression of the proinvasive factors laminin-5 gamma2 chain and MT1-MMP in colorectal carcinomas.
In colorectal carcinomas, loss-of-function mutations of the adenomatous polyposis coli (APC) tumor suppressor gene lead to a nuclear accumulation of the oncogenic transcriptional activator beta-catenin, predominantly at the invasive front within the tumor host interface. Various identified genes activated by beta-catenin are associated with tumor invasion. One prerequisite for malignant tumor invasion is the ability of tumor cells to migrate. We recently described the gamma2 chain of laminin as another beta-catenin target gene. Fragments of the laminin gamma2 chain, resulting from cleavage by the membrane type 1 matrix metalloproteinase (MT1-MMP), are strong inducers of epithelial cell migration. We here show a coordinated expression of nuclear beta-catenin, its target gene and MT1-MMP substrate laminin gamma2 chain, as well as MT1-MMP in tumor cells at invasive regions of colorectal carcinomas. We further demonstrate that MT1-MMP expression is regulated by beta-catenin/TCF through a TCF binding site in its promoter. These results suggest that nuclear beta-catenin activates the coordinated expression of the interacting proinvasive proteins laminin gamma2 chain and MT1-MMP, thereby leading to a promigratory activity at the invasive front of colorectal cancers. This further supports an important role of beta-catenin for invasion and metastasis of colorectal carcinomas.


Growth differentiation factor-9 and stem cell factor promote primordial follicle formation in the hamster: modulation by follicle-stimulating hormone.
Growth differentiation factor-9 (GDF-9) and stem cell factor (SCF) influence follicle formation beyond the primary stage; however, factors influencing the formation of primordial follicles remain elusive. To determine whether GDF-9 and SCF promoted primordial follicle formation during ovarian morphogenesis in the hamster, and whether FSH had any modulatory influence, fetal ovaries were collected on Gestation Day 15 from pregnant hamsters treated with or without an FSH antiserum on Gestation Day 12 and cultured in vitro up to Day 9 with SCF, GDF-9, or FSH. The percentages and diameters of primordial, primary, and secondary follicles and their oocytes were determined by morphometric evaluation, and the expression of GDF-9 was detected by immunolocalization. SCF, GDF-9, and FSH promoted primordial and primary follicle formation, but GDF-9 was more efficient. The diameters of the follicles developed under GDF-9 or FSH, but not SCF, compared well with those developed in vivo. FSH- and GDF-9-induced folliculogenesis was attenuated by the SCF antibody. Similarly, in vitro formation of primordial follicles decreased markedly in ovaries exposed to the FSH antiserum in utero, which was reversed by SCF, GDF-9, or FSH; however, GDF-9 had a profound effect on follicular development. GDF-9 protein appeared exclusively in the oocytes on Postnatal Day 4; however, it appeared in vitro by 48 h, and the expression was upregulated by FSH. These results suggest that although SCF-induced primordial follicle formation constitutes primarily somatic cell development, GDF-9 influences both the oocyte and its companion somatic cells. FSH plays an important role in primordial folliculogenesis in the hamster via GDF-9 and SCF.


A White Matter Fiber Microdissection Study of the Anterior Perforated Substance and the Basal Forebrain: A Gateway to the Basal Ganglia?
Studies detailing the anatomy of the basal forebrain (BF) from a neurosurgical perspective are missing. To describe the anatomy of the BF and of the anterior perforated substance (APS), the BF emphasizing surgical useful anatomical relationship between surface landmarks and deep structures. White matter fiber microdissection was performed on 5 brain specimens to analyze the topographic anatomy of the APS and expose layer-by-layer fiber tracts and nuclei of the BF. The APS, as identified anatomically, surgically, and neuroradiologically, has clear borders measured 23.3 ± 3.4 mm (19-27) in the mediolateral and 12.5 ± 1.2 mm (11-14) in the anteroposterior directions. A detailed stratigraphy of the BF was performed from the APS up to basal ganglia and thalamus allowing identification and dissection of the main components of the BF (septum, nucleus accumbens, amygdala, innominate substance) and its white matter tracts (band of Broca, extracapsular thalamic peduncle, ventral amygdalohypothalamic fibers). The olfactory trigone together with diagonal gyrus and the APS proper is a relevant superficial landmark for the basal ganglia (inferior to the nucleus accumbens, lateral to the caudate head, and medial to the lentiform nucleus). The findings in our study supplement available anatomic knowledge of APS and BF, providing reliable landmarks for precise topographic diagnosis of BF lesions and for intraoperative orientation. Surgically relevant relationships between surface and deep anatomic structures are highlighted offering thus a contribution to neurosurgeons willing to perform surgery in this delicate area.


Zerumbone from Zingiber zerumbet inhibits innate and adaptive immune responses in Balb/C mice.
Zerumbone exhibited various biological properties including in vitro immunosuppressive effects. However, its modulatory activity on the immune responses in experimental animal model is largely unknown. This investigation was conducted to explore the effects of daily treatment of zerumbone (25, 50, and 100 mg/kg) isolated from Zingiber zerumbet rhizomes for 14 days on various cellular and humoral immune responses in Balb/C mice. For measurement of adaptive immunity, sheep red blood cells (sRBC) were used to immunize the mice on day 0 and orally fed with similar doses of zerumbone for 14 days. The effects of zerumbone on phagocytosis, nitric oxide (NO) release, myeloperoxidase (MPO) activity, proliferation of T and B cells, lymphocyte phenotyping, cytokines release in serum by activated T cells, delayed type hypersensitivity (DTH) and immunoglobulins production (IgG and IgM) were investigated. Zerumbone downregulated the engulfment of E. coli by peritoneal macrophages and the release of NO and MPO in a concentration-dependent manner. Zerumbone showed significant and concentration-dependent suppression of T and B lymphocytes proliferation and inhibition of the Th1 and Th2 cytokines release. At higher concentrations of zerumbone, the % expression of CD4+ and CD8+ in splenocytes was significantly inhibited. Zerumbone also concentration-dependently demonstrated strong suppression on sRBC-triggered swelling of mice paw in DTH. Substantial suppression of anti-sRBC immunoglobulins antibody titer was noted in immunized and zerumbone-treated mice in a concentration-dependent manner. The potent suppressive effects of zerumbone on the immune responses suggest that zerumbone can be a potential candidate for development of immunosuppressive agent.


MR Imaging of the Achilles Tendon after Surgical Repair.
Achilles tendon tear is common and increasingly frequent. Magnetic resonance imaging (MRI) is the modality of choice for radiological evaluation. It is accurate to assess the status and integrity of the tendon with well documented features. In this article, the MR findings of a normal Achilles tendon as well as common diseases like insertional and noninsertional tendinosis, chronic tendinosis with marked lengthening, tendon rupture are illustrated. After a torn Achilles tendon receives surgical repair, it undergoes different stages of healing process including inflammatory, reparative and remodeling phases. Acute scar tissue in the surgical bed may share similar MR features of tendon re-rupture especially in the early healing phase because both are T2W hyperintense. The size of the gap may even appear larger than expected on T2W images possibly due to tendon remodeling. Understanding of the healing process in post-operative period may prevent overestimation of tendon gap and misdiagnosis of re-tear. We describe the MR features of the post-operative changes with serial studies in different months after surgery. The MR findings with the highlights of the expected sequential changes in normal healing process are illustrated in different cases. A case with surgical repair on a partial tear of Achilles tendon is also included.


Multivariate qualitative analysis of banned additives in food safety using surface enhanced Raman scattering spectroscopy.
A novel strategy which combines iteratively cubic spline fitting baseline correction method with discriminant partial least squares qualitative analysis is employed to analyze the surface enhanced Raman scattering (SERS) spectroscopy of banned food additives, such as Sudan I dye and Rhodamine B in food, Malachite green residues in aquaculture fish. Multivariate qualitative analysis methods, using the combination of spectra preprocessing iteratively cubic spline fitting (ICSF) baseline correction with principal component analysis (PCA) and discriminant partial least squares (DPLS) classification respectively, are applied to investigate the effectiveness of SERS spectroscopy for predicting the class assignments of unknown banned food additives. PCA cannot be used to predict the class assignments of unknown samples. However, the DPLS classification can discriminate the class assignment of unknown banned additives using the information of differences in relative intensities. The results demonstrate that SERS spectroscopy combined with ICSF baseline correction method and exploratory analysis methodology DPLS classification can be potentially used for distinguishing the banned food additives in field of food safety.


The effect of graded spinal cord injury on the extrapyramidal and pyramidal motor evoked potentials of the rat.
This study investigated the differential effects of graded spinal cord injury on the rat extrapyramidal motor evoked potential (exp-MEP) and pyramidal motor evoked potential (pyr-MEP) and the prognostic value of these effects in predicting postinjury motor performance in the rat model. In 20 rats subjected to graded spinal injury (10-100 g-cm), there was a differential injury threshold for ablation of exp-MEP and pyr-MEP. All peaks of the pyr-MEP were extinguished in the animals subjected to impact forces of 50 g-cm and above (n = 12). In contrast, the exp-MEP was completely abolished in only two animals at injuries of 80 g-cm or above. A residual exp-MEP response persisted in the remaining 18 animals. Motor performance was monitored in 16 additional animals for up to 1 week after spinal injury. The pyr-MEP was abolished in 100% of the rats subjected to a 50-g cm injury (n = 7), whereas the exp-MEP persisted up to the highest impact forces (80 g-cm). Hind leg paralysis was present in the five rats where the pyr-MEP was extinguished but with persistence of the exp-MEP. An 80% reduction in the amplitude of the pyr-MEP in four animals resulted in mild ataxia with motor improvement at the end of a week. An increase or a 70% loss in pyr-MEP peak amplitude resulted in no clinical motor deficits (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)


A clinician's guide to the use of gonadotropin-releasing hormone analogues in women.
Gonadotropin-releasing hormone (GnRH) and its analogues have been extensively used in clinical medicine since they were identified and synthesized in 1971. Native GnRH stimulates gonadotrophs of the anterior pituitary and has been used for induction of ovulation. The GnRH agonists, which have greater potency and a longer half-life than native GnRH, produce an initial stimulation of pituitary gonadotrophs that results in secretion of follicle-stimulating hormone and luteinizing hormone and the expected gonadal response. This response is followed by downregulation and inhibition of the pituitary-gonadal axis. The GnRH antagonists promptly suppress pituitary gonadotropin by GnRH-receptor competition, thereby avoiding the initial stimulatory phase of the agonists. Discontinuation of GnRH antagonist treatment leads to a rapid and predictable recovery of the pituitary-gonadal axis. The GnRH analogues are potent therapeutic agents that are considerably useful in a variety of clinical indications. These indications include management of endometriosis, uterine leiomyomas, hirsutism, dysfunctional uterine bleeding, premenstrual syndrome, assisted reproduction, and some hormone-dependent tumors.


Unintentional non-traffic injury and fatal events: Threats to children in and around vehicles.
There have been substantial reductions in motor vehicle crash-related child fatalities due to advances in legislation, public safety campaigns, and engineering. Less is known about non-traffic injuries and fatalities to children in and around motor vehicles. The objective of this study was to describe the frequency of various non-traffic incidents, injuries, and fatalities to children using a unique surveillance system and database. Instances of non-traffic injuries and fatalities in the United States to children 0-14 years were tracked from January 1990 to December 2014 using a compilation of sources including media reports, individual accounts from families of affected children, medical examiner reports, police reports, child death review teams, coroner reports, medical professionals, legal professionals, and other various modes of publication. Over the 25-year period, there were at least 11,759 events resulting in 3,396 deaths. The median age of the affected child was 3.7 years. The incident types included 3,115 children unattended in hot vehicles resulting in 729 deaths, 2,251 backovers resulting in 1,232 deaths, 1,439 frontovers resulting in 692 deaths, 777 vehicles knocked into motion resulting in 227 deaths, 415 underage drivers resulting in 203 deaths, 172 power window incidents resulting in 61 deaths, 134 falls resulting in 54 deaths, 79 fires resulting in 41 deaths, and 3,377 other incidents resulting in 157 deaths. Non-traffic injuries and fatalities present an important threat to the safety and lives of very young children. Future efforts should consider complementary surveillance mechanisms to systematically and comprehensively capture all non-traffic incidents. Continued education, engineering modifications, advocacy, and legislation can help continue to prevent these incidents and must be incorporated in overall child vehicle safety initiatives.


[Effect of Trichoderma species fungi on soil micromycetes, causing infectious conifer seedling lodging in Siberian tree nurseries].
Soils in the tree nurseries studied were characterized by a lower species diversity of fungi than adjacent virgin soils. In particular, the relative abundances of representatives of the genera Mucor, Chaetomium, and Trichoderma in the nursery soil were two times lower than in adjacent virgin soils. On the other hand, the nursery soil exhibited greater abundances of fungi of the genus Fusarium, which are causative agents of many diseases of conifer seedlings. To appreciate the efficiency of biocontrol of the infectious diseases of conifer seedlings, we introduced several indigenous Trichoderma strains into the nursery soil and found that this affected the species composition of soil microflora considerably. Changes in the species composition of mycobiota beneficially influenced the phytosanitary state of soils and reduced the infectious lodging of conifer seedlings.


Blood-brain barrier opened by stimulation of the parasympathetic sphenopalatine ganglion: a new method for macromolecule delivery to the brain.
Drug delivery across the blood-brain barrier remains a significant challenge. Based on earlier findings, the authors hypothesized that parasympathetic innervation of the brain vasculature could be used to augment drug delivery to the brain. Using a craniotomy-cerebrospinal fluid superfusate paradigm in rats with an intravenous injection of tracer the authors demonstrated that stimulation of the postganglionic parasympathetic fibers of the sphenopalatine ganglion (SPG) increased the concentration of fluorescein isothiocyanate-dextran (4-250 kD) in the superfusate by two- to sixfold. A histological examination indicated the presence of dextran in the parenchyma. In another experiment the amount of Evans blue dye in the brain following SPG activation was similarly significantly elevated. The chemotherapeutic agents anti-HER2 monoclonal antibody and etoposide were also delivered to the brain and reached therapeutic concentrations. Brain homeostasis was not disturbed by this procedure; a measurement of nicotinamide adenine dinucleotide reduction did not show a decrease in the tissue metabolic state and brain water content did not increase significantly. Sphenopalatine ganglion activation demonstrates a promising potential for clinical use in the delivery of small and large molecules to the brain.


Estimating axon conduction velocity in vivo from microstructural MRI.
The conduction velocity (CV) of action potentials along axons is a key neurophysiological property central to neural communication. The ability to estimate CV in humans in vivo from non-invasive MRI methods would therefore represent a significant advance in neuroscience. However, there are two major challenges that this paper aims to address: (1) Much of the complexity of the neurophysiology of action potentials cannot be captured with currently available MRI techniques. Therefore, we seek to establish the variability in CV that can be captured when predicting CV purely from parameters that have been reported to be estimatable from MRI: inner axon diameter (AD) and g-ratio. (2) errors inherent in existing MRI-based biophysical models of tissue will propagate through to estimates of CV, the extent to which is currently unknown. Issue (1) is investigated by performing a sensitivity analysis on a comprehensive model of axon electrophysiology and determining the relative sensitivity to various morphological and electrical parameters. The investigations suggest that 85% of the variance in CV is accounted for by variation in AD and g-ratio. The observed dependency of CV on AD and g-ratio is well characterised by the previously reported model by Rushton. Issue (2) is investigated through simulation of diffusion and relaxometry MRI data for a range of axon morphologies, applying models of restricted diffusion and relaxation processes to derive estimates of axon volume fraction (AVF), AD and g-ratio and estimating CV from the derived parameters. The results show that errors in the AVF have the biggest detrimental impact on estimates of CV, particularly for sparse fibre populations (AVF<0.3). For our equipment set-up and acquisition protocol, CV estimates are most accurate (below 5% error) where AVF is above 0.3, g-ratio is between 0.6 and 0.85 and AD is high (above 4μm). CV estimates are robust to errors in g-ratio estimation but are highly sensitive to errors in AD estimation, particularly where ADs are small. We additionally show CV estimates in human corpus callosum in a small number of subjects. In conclusion, we demonstrate accurate CV estimates are possible in regions of the brain where AD is sufficiently large. Problems with estimating ADs for smaller axons presents a problem for estimating CV across the whole CNS and should be the focus of further study.


Pleiotropic effects of a mutation in rfaC on Escherichia coli hemolysin.
Several genes involved in the lipopolysaccharide (LPS) biosynthetic pathway have been shown to affect the expression or activity of Escherichia coli hemolysin (Hly), a secreted cytotoxin that is the prototype of the RTX family of toxins. To further study this relationship, E. coli K-12 strains harboring mutations in the LPS biosynthetic genes rfaS, rfaQ, rfaJ, rfaP, and rfaC were transformed with a recombinant plasmid harboring the hlyCABD operon and examined for their effects on extracellular expression and hemolytic activity. A mutation in rfaC that affected both extracellular expression and activity of Hly was studied in greater detail. This mutation led to a growth-phase-dependent decrease up to 16-fold in the steady-state level of extracellular HlyA, although transcription and secretion of HlyA were decreased no more than 2-fold. Specific hemolytic activity in toxin produced from the rfaC mutant strain was significantly reduced, in a growth-phase-dependent manner. With the rfaC gene supplied in trans, both the decreased expression and activity of Hly were restored to wild-type levels. Hly from the rfaC mutant strain exhibited much slower kinetics of hemolysis, a more rapid rate of decay of activity, and greater formation of apparently inactive HlyA-containing aggregates in culture supernatants than was exhibited in the wild-type strain. A model is proposed for a physical interaction between LPS and Hly in which LPS with intact inner core participates in forming or maintaining an active conformation of Hly and helps to protect it from aggregation or degradation.


Altered fibular growth patterns after tibiofibular synostosis in children.
Iatrogenic synostosis of the tibia and fibula following an operation on the leg in a child has been reported rarely in the literature, and the effects of this complication on future growth, alignment, and function are not known. This is a retrospective case series, from one institution, of crossunions of the distal parts of the tibia and fibula complicating operations on the leg in children. The purpose is to alert surgeons to this possible complication. The senior author identified eight cases of iatrogenic tibiofibular synostosis seen in children since 1985. The patients had various diagnoses and were from the practices of four pediatric orthopaedic surgeons. Synostosis developed in six patients after osteotomies of the distal parts of the tibia and fibula, in one after internal fixation of distal tibial and fibular metaphyseal fractures through a single incision, and in one after posterior transfer of the anterior tibialis tendon through the interosseous membrane combined with peroneus brevis transfer to the calcaneus. Medical records were reviewed, and preoperative and follow-up radiographs were analyzed for changes in the relative positions of the proximal and distal tibial and fibular physes and in the alignment of the ankle. Five patients were symptomatic after crossunion; they presented with prominence of the proximal part of the fibula, ankle deformity, or ankle pain. Three patients were asymptomatic, and a synostosis was identified on routine follow-up radiographs. Intraoperative technical errors caused two of the crossunions; the cause of the others was unknown. Following tibiofibular synostosis, growth disturbances were noted radiographically in every patient. The normal growth pattern of distal migration of the fibula relative to the tibia was reversed, resulting in a decreased distance between the proximal physes of the tibia and fibula as well as proximal migration of the distal fibular physis relative to the distal part of the tibia. Shortening of the lateral malleolus led to greater valgus alignment of the ankle. Tibiofibular synostosis can complicate an operation on the leg in a child. After crossunion, the normal distal movement of the fibula relative to the tibia is disrupted, resulting in shortening of the lateral malleolus and ankle valgus as well as prominence of the fibular head at the knee. The synostosis also interferes with the normal motion that occurs between the tibia and fibula with weight-bearing, potentially leading to ankle pain.


Effect of clomiphene citrate on the synthesis and release of the human beta-lactoglobulin homologue, pregnancy associated endometrial alpha 2-globulin, by the uterine endometrium.
As an extension to a previous study to examine the effects of clomiphene citrate (CC) on human chorionic gonadotrophin/luteinizing hormone (LH) receptors in human corpora lutea, we sought to determine the effect of CC on the synthesis of the beta-lactoglobulin homologue, pregnancy associated endometrial alpha 2-globulin (alpha 2-PEG) by the luteal phase human endometrium. Seventeen normally-cycling women aged 25.9 +/- 2.1 years (mean +/- SE), undergoing elective tubal ligation, were divided into four groups consisting of controls (n = 2) and three treatment groups. Each of the treatment groups (n = 5/group) was treated with either 50 mg (group 1), 100 mg (group 2) or 150 mg (group 3) of CC daily on days 5 to 9 of the cycle. Portions of endometrial tissue were obtained by curettage 7 to 9 days following the urinary LH surge and were either fixed for histological analyses or cultured in vitro in the presence of [35S]methionine. Tissue media (TCM) that were analysed by two-dimensional gel electrophoresis followed by fluorography indicated that the synthesis of alpha 2-PEG was most markedly reduced in groups 2 and 3. Densitometric scans of TCM Western blots and radioimmunoassay (RIA) of TCM showed that the overall synthesis of alpha 2-PEG decreased from 5.8 +/- 1.9 arbitrary units (AU) and 371.2 +/- 239.3 ng/ml in group 1 to 3.1 +/- 0.8 AU and 69.4 +/- 24.9 ng/ml, and 2.7 +/- 1.1 AU and 52.4 +/- 19.8 ng/ml in groups 2 and 3 respectively. On cycle days 20-22, control values were 5.8 AU and 498.1 ng/ml respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Phosphodiesterase isoenzymes in human ureteral smooth muscle: identification, characterization, and functional effects of various phosphodiesterase inhibitors in vitro.
Phosphodiesterases (PDE) are key enzymes regulating intracellular cyclic nucleotide metabolism and, thus, contraction and relaxation of the muscle. At present, five different families of isoenzymes of PDE exist that show a distinct species-specific and organ-specific distribution. The aim of the present study was to analyze the PDE isoenzymes present in the human ureter and to evaluate the functional effects of isoenzyme-specific inhibitors in this tissue. Normal ureteral tissue was obtained during radical nephrectomies, homogenized, centrifuged, and the supernatant fraction was separated using DEAE-Sephacel anion-exchange chromatography. PDE assay was then performed and the isoenzymes characterized on the basis of their kinetic characteristics and their sensitivity to allosteric modulators and inhibitors. In vitro, longitudinal ureteral strips as well as ureteral rings were precontracted, and different selective and nonselective PDE inhibitors were added incrementally. Three different PDE isoenzymes were identified: PDE I (Ca/calmodulin-stimulated), PDE II (cyclic guanosine monophosphate-stimulated), and PDE IV (cyclic adenosine monophosphate-specific). All PDE inhibitors relaxed the strips dose-dependently with an EC50 of 30 microM for papaverine, 40 microM for zaprinast, 25 microM for quazinone, and 0.1 microM for rolipram. The existence of three different PDE isoenzymes was shown in this study. The ureter-relaxing effect of the PDE IV inhibitor at low concentrations, combined with its low effect on the systemic circulatory parameters, may open a possibility of using selective PDE IV inhibitors in the treatment of ureteral colics or ureteral stones.


Clinical Management of Nasal Skin Necrosis Caused by Hyaluronic Acid Filler.
Nose augmentation with Hyaluronic acid (HA) fillers has been considered the preferred technique for minimally invasive cosmetic procedures. Despite severe complications related to HA injection are rare, none of the existing treatment protocols has been established as standard. The aim of this report is to present an alternative approach to treat nasal skin necrosis related to HA injection. A high dose of hyaluronidase - 6000 IU was applied in the nose, for the purpose of reversing a necrotic process. The present findings suggest that a high dose of hyaluronidase could be a promising approach to treat severe nasal skin necrosis caused by HA filler.


Navigation Patterns and Scent Marking: Underappreciated Contributors to Hippocampal and Entorhinal Spatial Representations?
According to the currently prevailing theory, hippocampal formation constructs and maintains cognitive spatial maps. Most of the experimental evidence for this theory comes from the studies on navigation in laboratory rats and mice, typically male animals. While these animals exhibit a rich repertoire of behaviors associated with navigation, including locomotion, head movements, whisking, sniffing, raring and scent marking, the contribution of these behavioral patterns to the hippocampal spatially-selective activity has not been sufficiently studied. Instead, many publications have considered animal position in space as the major variable that affects the firing of hippocampal place cells and entorhinal grid cells. Here we argue that future work should focus on a more detailed examination of different behaviors exhibited during navigation to better understand the mechanism of spatial tuning in hippocampal neurons. As an inquiry in this direction, we have analyzed data from two datasets, shared online, containing recordings from rats navigating in square and round arenas. Our analyses revealed patchy navigation patterns, evident from the spatial maps of animal position, velocity and acceleration. Moreover, grid cells available in the datasets exhibited similar periodicity as the navigation parameters. These findings indicate that activity of grid cells could affect navigation parameters and/or vice versa. Additionally, we speculate that scent marks left by navigating animals could contribute to neuronal responses while rats and mice sniff their environment; the act of sniffing could modulate neuronal discharges even in virtual visual environments. Accordingly, we propose that future experiments should contain additional controls for navigation patterns, whisking, sniffing and maps composed of scent marks.


Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer.
ABI-007 is a novel nanoparticle, albumin-bound paclitaxel that is free of solvents. This multicenter phase II study was designed to evaluate the efficacy and safety of ABI-007 for the treatment of metastatic breast cancer (MBC). Sixty-three women with histologically confirmed and measurable MBC received 300 mg/m2 ABI-007 by intravenous infusion over 30 minutes every 3 weeks without premedication. Forty-eight patients received prior chemotherapy; 39 patients received no prior treatment for metastatic disease. Overall response rates (complete or partial responses) were 48% (95% CI, 35.3% to 60.0%) for all patients. For patients who received ABI-007 as first-line and greater than first-line therapy for their metastatic disease, the respective response rates were 64% (95% CI, 49.0% to 79.2%) and 21% (95% CI, 7.1% to 42.1%). Median time to disease progression was 26.6 weeks, and median survival was 63.6 weeks. No severe hypersensitivity reactions were reported despite the lack of premedication. Toxicities observed were typical of paclitaxel and included grade 4 neutropenia (24%), grade 3 sensory neuropathy (11%), and grade 4 febrile neutropenia (5%). Patients received a median of six treatment cycles; 16 patients had 25% dose reductions because of toxicities, and two of these patients had subsequent dose reductions. ABI-007, the first biologically interactive albumin-bound form of paclitaxel in the nanoparticle state, uses the natural carrier albumin rather than synthetic solvents to deliver paclitaxel and allows for safe administration of high paclitaxel doses without premedication, resulting in significant antitumor activity in patients with MBC, including those receiving the drug as first-line therapy.


Using social networks to reach Black MSM for HIV testing and linkage to care.
Black men who have sex with men (MSM) are disproportionately affected by HIV infection. Black MSM in San Francisco may have higher rates of unrecognized HIV infections. Increased HIV testing among Black MSM may reduce the numbers of unrecognized infections, inform more men of their status and thus reduce the potential for ongoing transmissions. Social network HIV testing programs have focused on asking HIV-positive and/or high-risk negative men to recruit their social or sexual contacts. We used a network approach to deliver HIV testing to Black MSM in San Francisco and collected risk assessment data. Participants were asked to recruit any of their social contacts who were also Black MSM. Recruitment by risk level and HIV status was heterogeneous. HIV infection among this population is associated with older age, having a high school education or higher and currently being homeless. Fully 23% of HIV positive Black MSM are unaware of their infection. Only a third of unrecognized infections were recruited by a known HIV-positive participant. Linkage to care was a challenge and underscores the need for comprehensive systems and support to link Black MSM to care and treatment.


Patients with cancer and sepsis trials: an unfair representation?
Approximately 20% of sepsis cases are thought to occur in patients with cancer. Thus, such patients are an important cohort to be represented and characterised among sepsis trials. However, patients with cancer are commonly excluded from sepsis trials, although the extent to which is unknown. In this opinion article, we discuss our findings that suggest that patients with cancer are being under-represented in sepsis trials, often with an unclear rationale. We question the validity of generalising results from sepsis trials to heterogenous cancer populations and call for wider inclusion of patients with cancer to bridge this knowledge gap in sepsis management.


5 Year old girl with malignant lymphoblastic lymphoma: challenges of managing haematological malignancies in a developing country.
Lymphoblastic lymphoma (LBL) is a neoplasm of lymphoblasts. The condition is predominantly lymph node-based disease arising from immature T cells in 85-90% of cases and immature B cells in the remainder. The lymphoma is aggressive, progresses rapidly, and often presenting as stage IV disease in more than 70% of patients. This disease makes up approximately 20% of childhood NHL. To show case the management of childhood lymphoblastic lymphoma and the handicap faced by the oncologists and pathologists. A review of the index case was carried out at the paediatric department of Federal Medical Centre, Bida, Nigeria. This review took into cognisance patient's demographic bio data, case history, general and physical examination, various investigations, methods of diagnosis and the type treatment. A comprehensive analysis and account of events before and after the commencement of chemotherapy were also reviewed. This case identifies a 5 year old girl with aggressive malignant lymphoma; lymphoblastic type and the myriad of limitations faced by oncologists and pathologists in the management of haematological malignancies. Socio-cultural, financial (cost implications for the patient for both investigative and therapeutic interventions), inadequate resources and facilities were identified as some of the constraints leading to inadequate management and poor outcome in patients with this condition. Given the limitations associated with the management of cancers in this part of the world, efforts on the part of government and non-governmental agencies are necessary to strengthen and upgrade the existing facilities in various hospitals. The social welfare departments of tertiary hospitals should be adequately funded to meet the demand of this group of patients.


A setup for element specific magnetization dynamics using the transverse magneto-optic Kerr effect in the energy range of 30-72 eV.
In this paper, we present a spectrometer that is designed for element-specific and time-resolved transverse magneto-optic Kerr effect experiments at the high-harmonic generation pump-probe facility High Energy Laser Induced Overtone Source (HELIOS) laboratory. HELIOS delivers photons with energies between 30 eV and 72 eV with an overall time resolution of less than 40 fs. The spectrometer is based on a Rowland-circle geometry and allows for simultaneous measurements of all magnetic transition-metal elements. The setup also features easy sample transfer and alignment, and it combines high photon throughput, optimized data acquisition, and a fast switching of the magnetic field at the sample. The spectrometer performance is demonstrated by measuring the ultrafast demagnetization of permalloy. Our data are, for all practical purposes, identical to what have been reported in the earlier high-order harmonic generation work of a similar sample by Mathias et al. [Proc. Natl. Acad. Sci. U. S. A. 109, 4792-4797 (2012)], however, obtained within 15% of the acquisition time compared to their study. Furthermore, our data show a shift of the demagnetization curve of Ni relative to Fe, which has previously been interpreted as a delay of the Ni demagnetization to that of Fe [S. Mathias et al., Proc. Natl. Acad. Sci. U. S. A. 109, 4792-4797 (2012)].


Quantitative proteomics of tissue infiltrating T cells from CRC patients identified Lipocalin-2 induces T cell apoptosis and promotes tumor cell proliferation by iron efflux.
T cells play the most pivotal roles in anti-tumor immunity, the T cell proteome and the differentially expressed proteins (DEPs) in the tumor immune microenvironment have rarely been identified directly from the clinical samples, especially for tumors that lack effective immunotherapy targets, such as colorectal cancer (CRC). In this study, we analyzed the protein expression pattern of the infiltrating T cells isolated from CRC patients using quantitative proteomics. CD4+ and CD8+ T cells were isolated from clinical samples and labeled by TMT reagents, and the DEPs were quantified by mass spectrometry. The T cell proteome profiling revealed dysfunctions in these tumor-infiltrating T cells. Specifically, anti-tumor immunity was suppressed due to differentially expressed metal ion transporters and immunity regulators. For the first time, Lipocalin-2 (LCN2) was shown to be significantly up-regulated in CD4+ T cells. Quantitative proteomic analysis of LCN2-overexpressed Jurkat cells showed that LCN2 damaged T cells by changes in iron transport. LCN2 induced T cell apoptosis by reducing cellular iron concentration; moreover, the iron that was transported to the tumor microenvironment aided tumor cell proliferation, promoting tumor development. Meanwhile, LCN2 also influenced tumor progression through immune cytokines and cholesterol metabolism. Our results demonstrated that LCN2 has immunosuppressive functions that can promote tumor development; therefore, it is a potential immunotherapy target for CRC.


Establishment of a Heterologous RNA Editing Event in Chloroplasts.
In chloroplasts and plant mitochondria, specific cytidines in mRNAs are posttranscriptionally converted to uridines by RNA editing. Editing sites are recognized by nucleus-encoded RNA-binding proteins of the pentatricopeptide repeat (PPR) family, which bind upstream of the editing site in a sequence-specific manner and direct the editing activity to the target position. Editing sites have been lost many times during evolution by C-to-T mutations. Loss of an editing site is thought to be accompanied by loss or degeneration of its cognate PPR protein. Consequently, foreign editing sites are usually not recognized when introduced into species lacking the site. Previously, the spinach (Spinacia oleracea) psbF-26 editing site was introduced into the tobacco (Nicotiana tabacum) plastid genome. Tobacco lacks the psbF-26 site and cannot edit it. Expression of the "unedited" PsbF protein resulted in impaired PSII function. In Arabidopsis (Arabidopsis thaliana), the PPR protein LPA66 is required for editing at psbF-26. Here, we show that introduction of the Arabidopsis LPA66 reconstitutes editing of the spinach psbF-26 site in tobacco and restores a wild-type-like phenotype. Our findings define the minimum requirements for establishing new RNA editing sites and suggest that the evolutionary dynamics of editing patterns is largely explained by coevolution of editing sites and PPR proteins.


DW14383 is an irreversible pan-FGFR inhibitor that suppresses FGFR-dependent tumor growth in vitro and in vivo.
Fibroblast growth factor receptor (FGFR) is a promising anticancer target. Currently, most FGFR inhibitors lack sufficient selectivity and have nonnegligible activity against kinase insert domain receptor (KDR), limiting their feasibility due to the serious side effects. Notably, compensatory activation occurs among FGFR1-4, suggesting the urgent need to develop selective pan-FGFR1-4 inhibitors. Here, we explored the antitumor activity of DW14383, a novel irreversible FGFR1-4 inhibitor. DW14383 exhibited equivalently high potent inhibition against FGFR1, 2, 3 and 4, with IC50 values of less than 0.3, 1.1, less than 0.3, and 0.5 nmol/L, respectively. It is a selective FGFR inhibitor, exhibiting more than 1100-fold selectivity for FGFR1 over recombinant KDR, making it one of the most selective FGFR inhibitors over KDR described to date. Furthermore, DW14383 significantly inhibited cellular FGFR1-4 signaling, inducing G1/S cell cycle arrest, which in turn antagonized FGFR-dependent tumor cell proliferation. In contrast, DW14383 had no obvious antiproliferative effect against cancer cell lines without FGFR aberration, further confirming its selectivity against FGFR. In representative FGFR-dependent xenograft models, DW14383 oral administration substantially suppressed tumor growth by simultaneously inhibiting tumor proliferation and angiogenesis via inhibiting FGFR signaling. In summary, DW14383 is a promising selective irreversible pan-FGFR inhibitor with pan-tumor spectrum potential in FGFR1-4 aberrant cancers, which has the potential to overcome compensatory activation among FGFR1-4.


Modulation of aromatase expression in the breast tissue by ERR alpha-1 orphan receptor.
We have previously identified a silencer element (S1) that is situated between promoters I.3 and II of the human aromatase gene and that down-regulates the action of these promoters. We recently applied the yeast one-hybrid approach to screen a human breast tissue hybrid cDNA expression library for genes encoding the proteins binding to the silencer region. Most proteins identified from this approach belong to the nuclear receptor superfamily. Fifty % of the positive clones encode for ERR alpha-1, and other positive clones include EAR-2, EAR-3 (COUP-TF1), RAR gamma, and p120E4F. Because ERR alpha-1 was found to be the major protein interacting with S1, we decided to examine the regulatory action of ERR alpha-1 on promoter I.3 of the human aromatase gene. Using a reporter plasmid that includes the aromatase genomic fragment containing promoter I.3 and S1, ERR alpha-1 was found to have a positive regulatory function in breast cancer SK-BR-3 cells. Gel mobility shift assays have confirmed that ERR alpha-1 binds to S1 in a dose-dependent manner, and DNase I footprinting analysis has revealed that ERR alpha-1 binds to a region, 5'-AAGGTCAGAAAT-3', which is within S1 and between 96 and 107 bp relative to the transcriptional start site of promoter I.3. In addition, despite the fact that the nuclear receptor SF1 was shown previously to bind to the same site and to mediate a cAMP response in ovary, our yeast one-hybrid screening did not find any SF-1 clones. Gel mobility shift assays further revealed that SF-1 can bind to the silencer element with an affinity comparable with ERR alpha-1. Because our reverse transcription-PCR analysis was not able to detect SF1 mRNA in breast cancer tissue or in SK-BR-3 cells, it is thought that SF1 protein is not expressed in breast cancer tissue. Two ERR alpha-1 RNA variants with differences at the 5'-end have been reported. Our reverse transcription-PCR analysis identified the shorter variant in 28 of 32 breast tumor specimens and the longer variant in only 1 specimen. In addition, the shorter variant was detected in breast cancer SK-BR-3 cells as well as in a breast tumor fibroblast line WS3TF. The results suggest that ERR alpha-1 is one of the nuclear proteins interacting with S1 in breast cancer tissue. It is thought that the silencer element in the human aromatase gene may function differently in different tissues because of distinct expression patterns of transcription factors.


A guide to emollient therapy.
Although the benefits of emollient therapy have been widely acknowledged in dermatology treatments (Cork 1997), emollients have tended to be undervalued and under-used in general care and wound management. Healthy skin is an essential part of patient wellbeing, and emollient therapy is integral to the management of skin problems. The integration of tissue viability and dermatology services in the Plymouth Hospitals NHS Trust provided an opportunity to evaluate how and why emollient therapy is implemented. In practice, the authors have identified that healthcare practitioners need guidance and advice on emollient therapy to improve their care delivery. This article is based on the emollient therapy currently used in the authors' trust.


Mindfulness-based stress reduction to enhance psychological functioning and improve inflammatory biomarkers in trauma-exposed women: A pilot study.
This study examined the effects of a mindfulness-based stress reduction (MBSR) program on psychological functioning and inflammatory biomarkers in women with histories of interpersonal trauma. The 8-week MBSR program was conducted at a community-based health center and participants (N = 50) completed several measures of psychological functioning at study entry as well as 4 weeks, 8 weeks, and 12 weeks later. Inflammatory biomarkers were assayed from blood collected at each assessment. A series of linear mixed-model analyses were conducted to measure the effect of attendance and time on the dependent variables. Time was associated with significant decreases in perceived stress, depression, trait and state anxiety, emotion dysregulation, and posttraumatic stress symptoms, as well as increases in mindfulness. Session attendance was associated with significant decreases in interleukin (IL)-6 levels. This pilot study demonstrated the potential beneficial effects of MBSR on psychological functioning and the inflammatory biomarker IL-6 among trauma-exposed and primarily low-income women. Decreases in inflammation have implications for this population, as interpersonal trauma can instigate chronic physiological dysregulation, heightened morbidity, and premature death. This study's preliminary results support efforts to investigate biological remediation with behavioral interventions in vulnerable populations.


Inhibition of Interleukin-10 Signaling Induces Microbiota-dependent Chronic Colitis in Apolipoprotein E Deficient Mice.
Apolipoprotein E (ApoE) mediates potent antiinflammatory and immunomodulatory properties in addition to its roles in regulating cholesterol transport and metabolism. However, its role in the intestine, specifically during inflammation, is largely unknown. Mice (C57BL/6 or ApoE-deficient [ApoE-KO] mice) were administered either single or 4 injections (weekly) of anti-interleukin (IL)-10 receptor monoclonal antibody (1.0 mg/mouse; intraperitoneally) and euthanized 1 week after the last injection. 16S rRNA sequencing was performed in fecal samples to analyze the gut bacterial load and its composition. Microbiota was ablated by administration of broad-spectrum antibiotics in drinking water. IL-10KO mice were cohoused with ApoE-KO mice or their wild-type littermates to monitor the colitogenic potential of gut microbiota harbored in ApoE-KO mice. ApoE-KO mice developed severe colitis upon neutralization of IL-10 signaling as assessed by every parameter analyzed. 16S rRNA sequencing revealed that the ApoE-KO mice display elevated and altered gut microbiota that were accompanied with impaired production of intestinal antimicrobial peptides. Interestingly, microbiota ablation ameliorates colitis development in ApoE-KO mice. Exacerbated and accelerated colitis was observed in IL-10KO mice when cohoused with ApoE-KO mice. Our study highlights a novel interplay between ApoE and IL-10 in maintaining gut homeostasis and that such crosstalk may play a critical role in the pathogenesis of inflammatory bowel disease. Gut sterilization and the cohousing experiment suggest that microbiota play a pivotal role in the development of inflammatory bowel disease in mice lacking ApoE.


The role of indirect radionuclide cystography during the acute phase of pyelonephritis in young women.
To review our experience using dynamic 99mTc-diethylenetriamine penta-acetic acid renal scintigraphy combined with indirect radionuclide cystography (IRC) in the acute phase of pyelonephritis, as a possible alternative to the conventional imaging, as investigating acute pyelonephritis usually includes imaging the upper urinary tract during the acute phase, to exclude obstruction, and delayed voiding cysto-urethrography (VCUG) when underlying vesico-ureteric reflux (VUR) is suspected. Between 1997 and 1999, 47 young women (median age 22 years, range 18-37) were hospitalized for acute pyelonephritis. The combined study was used during the acute phase of the disease, usually within 24 h of hospitalization. The principle of IRC is based on the reappearance of radioactivity in the ureters or kidneys after previously detecting renal clearance of an intravenously injected radioisotope. The increase in radioactivity over the ureters or kidneys indicates VUR. The subsequent follow-up included VCUG, after recovery and at least 6 weeks after discharge. Overall, 47 patients had early IRC studies; obstruction of the urinary tract during the acute phase of the disease was excluded in all. In 13 (28%) of the patients early IRC studies showed VUR involving 21 upper tract units. The renal parenchymal scan was impaired in 17 (36%) patients, and six of these 17 also had detectable concomitant reflux on IRC. Overall, 24 IRC studies (51%) were considered positive, showing VUR, renal parenchymal pathology or both; 23 (49%) were normal. Follow-up VCUG was used in 32 patients (68%); only three (9%) detected VUR. All of the patients with VUR on follow-up VCUG had also had an abnormal early IRC study, showing either reflux (two) or findings suggestive of pathological renal parenchyma (one). In addition to the well-established role of renal scintigraphy in excluding obstruction of the collecting system, early IRC is characterized by high sensitivity and accurate negative predictive value for detecting VUR. It can therefore be used to screen adults presenting with acute pyelonephritis for the presence of VUR. Patients with an abnormal IRC require follow-up VCUG after complete recovery, while those with a negative study may be managed expectantly, with no further radiological evaluation. This proposed strategy may avoid up to half of the delayed VCUG studies, preclude the related inconvenience, and substantially reduce the costs.


Marginalization and social change processes among lesbian, gay, bisexual and transgender persons in Swaziland: implications for HIV prevention.
Swaziland has among the highest national adult HIV prevalence globally. There is limited knowledge of HIV vulnerabilities and prevention engagement among lesbian, gay, bisexual and transgender (LGBT) persons in the context of Swaziland's criminalization of consensual same-sex practices. This study explored social processes of marginalization to assess how they could potentiate HIV vulnerabilities and limit engagement in HIV prevention services. Additionally, we assessed positive change to better understand existing strategies employed by LGBT persons to challenge these HIV prevention barriers. Guided by community-based research methodology and conducted in Mbabane and Manzini, Swaziland, data were collected by LGBT peer-research assistants (PRA) in collaboration with an LGBT community organization in Manzini. Semi-structured interviews were conducted by trained PRAs and explored HIV prevention, including experiences of stigma and coping. Audio files were transcribed verbatim, translated to English, and analyzed using thematic techniques. Among participants (n = 51; mean age: 26.47, SD: 4.68), 40 self-identifed as gay or lesbian (78.4%), 11 bisexual (22.6%), and 12 (23.5%) identified as transgender. Findings highlighted three primary processes of marginalization and positive change in structural, community, and internal domains. First, structural marginalization, which included criminalization, healthcare discrimination, and a scarcity of LGBT tailored HIV prevention resources was challenged by grassroots networks created to access and share specific HIV resources with LGBT persons and the Ministry of Health. Second, community marginalization included stigma and multi-dimensional forms of violence, however, this was met with LGBT persons providing mutual peer support, including for accessing HIV testing services. Thirdly, internal marginalization comprised of self-stigma and associated sexual risk practices was contrasted with coping strategies focused on self-acceptance, stemming from social support and leading to healthcare utilization. Jointly, these findings can inform the implementation of community-based and rights affirming HIV prevention and care cascade strategies that improve coverage of services with LGBT persons in Swaziland.