Effects of treadmill exercise and sex hormones on learning, memory and hippocampal brain-derived neurotrophic factor levels in transient congenital hypothyroid rats.
Transient thyroid function abnormalities at birth exhibit intellectual developmental and cognitive disorders in adulthood. Given the well-known effects of physical activity and sex hormones on cognitive functions and brain-derived neurotrophic factor (BDNF), the present study examined the effects of treadmill exercise, sex hormones, and the combined treatment on learning and memory and hippocampal BDNF levels in transient congenital hypothyroid rats. To induce hypothyroidism, 6-propyl-2-thiouracil was added to the drinking water from the 6th day of gestation to the 21st postnatal day (PND). From PNDs 28 to 47, female and male pup rats received 17β-estradiol and testosterone, respectively, and about 30 min later, they were forced to run on the treadmill for 30 min once a day. On PNDs 48-55, spatial learning and memory of all rats tested in the water maze, which followed by measurement of BDNF in the hippocampus. Results showed that developmental hypothyroidism induced significant deficits in spatial learning and memory and hippocampal BDNF in both male and female rats. In both male and female hypothyroid rats, exercise and exercise plus sex hormones, but not sex hormones alone alleviated learning and memory deficits and all treatments (exercise, sex hormones, and the combined treatment) increased hippocampal BDNF. These disconnects in the effects of exercise, sex hormones and the combined treatment on behavioral and neurochemical outcomes suggest that a neurochemical mechanism other than hippocampal BDNF might contribute in the ameliorating effects of exercise on learning and memory deficits induced by developmental thyroid hormone insufficiency.


Comparative atomic force and scanning electron microscopy: an investigation of structural differentiation of hepatic stellate cells.
The molecular mechanism leading to the transdifferentiation of hepatic stellate cells (HSC) into myofibroblast-like cells following liver injury is not well understood. The state of cultured rat HSCs was determined using primarily fluorescence microscopy (UV), immunofluorescence (IF) (Glial fibrillary acidic protein (GFAP), Desmin, alpha-smooth muscle actin (alpha-SMA), F-actin) and immunocytochemistry (ICC) (GFAP, Desmin, alpha-SMA, Fibulin-2). Additionally, tapping-mode atomic force microscopy (TM-AFM) and field-emission scanning electron microscopy (FE-SEM) with low-resistivity indium-tin-oxide (ITO) thin-film were performed to observe the micro-morphological character of cells during HSC differentiation. Quiescent HSCs changed to the activated state were identified via UV, IF, and ICC observations. Normal rat HSCs (NHSCs) and thioacetamide-induced rat HSCs (THSCs) were demonstrated to be UV(-), GFAP(+), Desmin(+), alpha-SMA(+) and Fibulin-2(-). After F-actin staining, lamellipodia and filopodia were found in both NHSCs and THSCs, but membrane ruffles were only seen in THSCs. The micro-structures of lamellipodia and filopodia in both NHSCs and THSCs were confirmed using FE-SEM and TM-AFM with ITO; in contrast, the micro-projection was not found. Moreover, "aerial root" structures were observed for the first time in the filopodia of THSCs using TM-AFM. These results reveal that HSC transdifferentiation to a myofibroblastic-like cell (activated HSC) from thioacetamide-induced rat HSC induces extensive changes in the cytoskeleton.


Predicting Autonomous Shuttle Acceptance in Older Drivers Based on Technology Readiness/Use/Barriers, Life Space, Driving Habits, and Cognition.
Shared autonomous vehicle services (i. e., automated shuttles, AS) are being deployed globally and may improve older adults (>65 years old) mobility, independence, and participation in the community. However, AS must be user friendly and provide safety benefits if older drivers are to accept and adopt this technology. Current potential barriers to their acceptance of AS include a lack of trust in the systems and hesitation to adopt emerging technology. Technology readiness, perceived ease of use, perceived barriers, and intention to use the technology, are particularly important constructs to consider in older adults' acceptance and adoption practices of AS. Likewise, person factors, i.e., age, life space mobility, driving habits, and cognition predict driving safety among older drivers. However, we are not sure if and how these factors may also predict older adults' intention to use the AS. In the current study, we examined responses from 104 older drivers (M age = 74.3, SD age = 5.9) who completed the Automated Vehicle User Perception Survey (AVUPS) before and after riding in an on-road automated shuttle (EasyMile EZ10). The study participants also provided information through the Technology Readiness Index, Technology Acceptance Measure, Life Space Questionnaire, Driving Habits Questionnaire, Trail-making Test Part A and Part B (TMT A and TMT B). Older drivers' age, cognitive scores (i.e., TMT B), driving habits (i.e., crashes and/or citations, exposure, and difficulty of driving) and life space (i.e., how far older adults venture from their primary dwelling) were entered into four models to predict their acceptance of AVs-operationalized according to the subscales (i.e., intention to use, perceived barriers, and well-being) and the total acceptance score of the AVUPS. Next, a partial least squares structural equation model (PLS-SEM) elucidated the relationships between, technology readiness, perceived ease of use, barriers to AV acceptance, life space, crashes and/or citations, driving exposure, driving difficulty, cognition, and intention to use AS. The regression models indicated that neither age nor cognition (TMT B) significantly predicted older drivers' perceptions of AVs; but their self-reported driving difficulty (p = 0.019) predicted their intention to use AVs: R 2 = 6.18%, F (2,101) = 4.554, p = 0.040. Therefore, intention to use was the dependent variable in the subsequent PLS-SEM. Findings from the PLS-SEM (R 2 = 0.467) indicated the only statistically significant predictors of intention to use were technology readiness (β = 0.247, CI = 0.087-0.411) and barriers to AV acceptance (β = -0.504, CI = 0.285-0.692). These novel findings provide evidence suggesting that technology readiness and barriers must be better understood if older drivers are to accept and adopt AS.


Development of a cancer genetics education program for clinicians.
There is a gap in knowledge about hereditary cancer and genetic testing among primary care practitioners. Education is needed to enable identification and management of patients at high risk for cancer. A new cancer genetics curriculum was delivered through individual lectures and full-day conferences. Innovative marketing and conference organizational approaches were used to increase participation. The curriculum has been delivered to 7,400 health care professionals with diverse educational backgrounds. Conventional formats were successfully used to implement this new curriculum. CME evaluations indicated satisfaction with the programs and a clear need for and continued interest in cancer genetics applications.


No association between the 20210 G/A prothrombin gene mutation and premature coronary artery disease.
The 20210 G/A prothrombin gene mutation is associated with an increased risk of venous thrombosis but whether there is an association of the mutation with premature coronary artery disease and acute myocardial infarction remains unclear. To further assess the role of the G/A genotype as a risk factor for arterial vascular disease, we performed a case-control study of 644 patients aged less than 50 years with angiographically proven coronary artery disease, 402 of whom had myocardial infarction, and 679 unrelated healthy control subjects aged less than 50 years, randomly selected from the electoral roll. The prevalence of the G/A genotype was 2.5% in patients with coronary artery disease, and 3.2% in control subjects (odds ratio 0.8; 95% confidence interval 0.35 to 1.83). The mutation was not more frequent among patients with a history of myocardial infarction (2.2%, odds ratio 0.7; 95% confidence interval 0.27 to 2.05), and there was no evidence of an interaction between the prothrombin mutation and conventional cardiovascular disease risk factors. There was no association between genotype and extent of angiographic coronary artery disease (p=0.73). We conclude that the 20210 G/A prothrombin gene mutation is not a major risk factor for premature coronary artery disease in our predominantly Caucasian Australian population.


Measurement of tactile allodynia in a murine model of bacterial prostatitis.
Uropathogenic Escherichia coli (UPEC) are pathogens that play an important role in urinary tract infections and bacterial prostatitis. We have recently shown that UPEC have an important role in the initiation of chronic pelvic pain, a feature of Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS). Infection of the prostate by clinically relevant UPEC can initiate and establish chronic pain through mechanisms that may involve tissue damage and the initiation of mechanisms of autoimmunity. A challenge to understanding the pathogenesis of UPEC in the prostate is the relative inaccessibility of the prostate gland to manipulation. We utilized a previously described intraurethral infection method to deliver a clinical strain of UPEC into male mice thereby establishing an ascending infection of the prostate. Here, we describe our protocols for standardizing the bacterial inoculum as well as the procedure for catheterizing anesthetized male mice for instillation of bacteria. CP/CPPS is primarily characterized by the presence of tactile allodynia. Behavior testing was based on the concept of cutaneous hyperalgesia resulting from referred visceral pain. An irritable focus in visceral tissues reduces cutaneous pain thresholds allowing for an exaggerated response to normally non-painful stimuli (allodynia). Application of normal force to the skin result in abnormal responses that tend to increase with the intensity of the underlying visceral pain. We describe methodology in NOD/ShiLtJ mice that utilize von Frey fibers to quantify tactile allodynia over time in response to a single infection with UPEC bacteria.


LOXL3-sv2, a novel variant of human lysyl oxidase-like 3 (LOXL3), functions as an amine oxidase.
Human lysyl oxidase-like 3 (LOXL3) functions as a copper-dependent amine oxidase toward collagen and elastin. The LOXL3 protein contains four scavenger receptor cysteine-rich (SRCR) domains in the N-terminus in addition to the C-terminal characteristic domains of the lysyl oxidase (LOX) family, such as a copper-binding domain, a cytokine receptor‑like domain and residues for the lysyl-tyrosyl quinone cofactor. Using BLASTN searches, we identified a novel variant of LOXL3 (termed LOXL3-sv2), which lacked the sequences corresponding to exons 4 and 5 of LOXL3. The LOXL3-sv2 mRNA is at least 2,398 bp in length, encoding a 608 amino acid-long polypeptide with a calculated molecular mass of 67.4 kDa. The deletion of exons 4 and 5 do not change the open-reading frame of LOXL3 but results in deletion of the SRCR domain 2. The recombinant LOXL3-sv2 protein showed a β-aminopropionitrile-inhibitable amine oxidase activity toward collagen type I. In RT-PCR analysis, LOXL3-sv2 was detected in all human tissues tested, along with LOXL3 and LOXL3-sv1, a previously identified variant of LOXL3. These findings indicate that the human LOXL3 gene encodes at least three variants, LOXL3, LOXL3-sv1 and LOXL3-sv2, all of which function as amine oxidases.


The pan-inhibitor of Aurora kinases danusertib induces apoptosis and autophagy and suppresses epithelial-to-mesenchymal transition in human breast cancer cells.
Danusertib (Danu) is a pan-inhibitor of Aurora kinases and a third-generation breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (Bcr-Abl) tyrosine kinase inhibitor, but its antitumor effect and underlying mechanisms in the treatment of human breast cancer remain elusive. This study aimed to investigate the effects of Danu on the growth, apoptosis, autophagy, and epithelial-to-mesenchymal transition (EMT) and the molecular mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. The results demonstrated that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both breast cancer cell lines. Danu arrested MCF7 and MDA-MB-231 cells in G2/M phase, accompanied by the downregulation of cyclin-dependent kinase 1 and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53. Danu significantly decreased the expression of B-cell lymphoma-extra-large (Bcl-xl) and B-cell lymphoma 2 (Bcl-2), but increased the expression of Bcl-2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and promoted the cleavage of caspases 3 and 9. Furthermore, Danu significantly increased the expression levels of the membrane-bound microtubule-associated protein 1A/1B-light chain 3 (LC3-II) and beclin 1 in breast cancer cells, two markers for autophagy. Danu induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1 and 2 (Erk1/2) and inhibited the activation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in breast cancer cells. Treatment with wortmannin (a phosphatidylinositol 3-kinase inhibitor) markedly inhibited Danu-induced activation of p38 MAPK and conversion of cytosolic LC3-I to membrane-bound LC3-II. Pharmacological inhibition and small interfering RNA-mediated knockdown of p38 MAPK suppressed Akt activation, resulting in LC3-II accumulation and enhanced autophagy. Pharmacological inhibition and small interfering RNA-mediated knockdown of Erk1/2 also remarkably increased the level of LC3-II in MCF7 cells. Moreover, Danu inhibited EMT in both MCF7 and MDA-MB-231 cells with upregulated E-cadherin and zona occludens protein 1 (ZO-1) but downregulated N-cadherin, zinc finger E-box-binding homeobox 1 (TCF8/ZEB1), snail, slug, vimentin, and β-catenin. Notably, Danu showed lower cytotoxicity toward normal breast epithelial MCF10A cells. These findings indicate that Danu promotes cellular apoptosis and autophagy but inhibits EMT in human breast cancer cells via modulation of p38 MAPK/Erk1/2/Akt/mTOR signaling pathways. Danu may represent a promising anticancer agent for breast cancer treatment. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Danu in breast cancer therapy.


Construction of CPs@MnO2-AgNPs as a multifunctional nanosensor for glutathione sensing and cancer theranostics.
A multifunctional nanosensor of CPs@MnO2-AgNPs was constructed for sensitive and selective sensing of GSH and cancer theranostics in this work. The CPs@MnO2 nanocomposite was synthesized by capping MnO2 onto carbon nanoparticles through an in situ redox reaction under ultrasonication. AgNPs with fluorescence were obtained through a silver-mirror-like reaction using BSA as both a template and reductant and further anchored onto the surface of CPs@MnO2 through electrostatic interaction to construct the CPs@MnO2-AgNP nanocomposite. The fluorescence of AgNPs was effectively quenched by MnO2 through an inner filter effect and a static quenching effect and further recovered by GSH owing to the unique redox reaction between GSH and MnO2. Therefore, a novel fluorescent turn-on nanosensor was established for GSH sensing in vitro and in vivo. For GSH sensing, a satisfactory linear range of 0.8-80 μM with a detection limit of 0.55 μM was obtained under optimal conditions. Moreover, by integrating the GSH-responsive fluorescence imaging capacity, the photothermal activity of carbon nanoparticles and the anticancer effect of AgNPs, the CPs@MnO2-AgNP nanocomposite was successfully applied for cancer theranostics. The fluorescence recognition of cancer was achieved by overexpressing GSH in cancer, meanwhile the photothermal therapy from CPs and chemotherapy from AgNPs jointly produced an enhanced therapeutic effect. This redox-responsive nanocomposite of CPs@MnO2-AgNPs improves the MnO2 nanomaterial-based applications in GSH sensing and cancer theranostics.


The DNA methylome and transcriptome of different brain regions in schizophrenia and bipolar disorder.
Extensive changes in DNA methylation have been observed in schizophrenia (SC) and bipolar disorder (BP), and may contribute to the pathogenesis of these disorders. Here, we performed genome-scale DNA methylation profiling using methylated DNA immunoprecipitation followed by sequencing (MeDIP-seq) on two brain regions (including frontal cortex and anterior cingulate) in 5 SC, 7 BP and 6 normal subjects. Comparing with normal controls, we identified substantial differentially methylated regions (DMRs) in these two brain regions of SC and BP. To our surprise, different brain regions show completely distinct distributions of DMRs across the genomes. In frontal cortex of both SC and BP subjects, we observed widespread hypomethylation as compared to normal controls, preferentially targeting the terminal ends of the chromosomes. In contrast, in anterior cingulate, both SC and BP subjects displayed extensive gain of methylation. Notably, in these two brain regions of SC and BP, only a few DMRs overlapped with promoters, whereas a greater proportion occurs in introns and intergenic regions. Functional enrichment analysis indicated that important psychiatric disorder-related biological processes such as neuron development, differentiation and projection may be altered by epigenetic changes located in the intronic regions. Transcriptome analysis revealed consistent dysfunctional processes with those determined by DMRs. Furthermore, DMRs in the same brain regions from SC and BP could successfully distinguish BP and/or SC from normal controls while differentially expressed genes could not. Overall, our results support a major role for brain-region-dependent aberrant DNA methylation in the pathogenesis of these two disorders.


[Disseminated metastatic tumor at dorsal surface of medulla oblongata presenting intractable hiccups. A case report].
We report the case of disseminated metastatic tumor at dorsal surface of medulla oblongata presenting intractable hiccups. A 73-year-old man has a history of for metastatic lung tumor of the left tempral lobe. Although 3 surgeries and 4 radiotherapies were performed in the last 8 years, residual tumor grew slowly. He presented with intractable hiccups. His hiccups continued for 30 minutes, sometimes for 3 hours with obstruction of eating. Contrast-enhanced Magnetic resonance (MR) imaging demonstrated the dissemination of metastatic lung tumor at dorsal surface of medulla oblongata and ventral surface of midbrain. Some literatures reported the patients with intractable hiccups caused by dorsal medullary lesions. Therefore, we thought that the small disseminated tumor at dorsal surface of medulla oblongata caused the hiccups. Evaluation of dorsal medullay area by MR imaging is important to reveal the cause of intractable hiccups.


Psychological interventions to improve pain, fatigue, anxiety, depression, and quality of life in children and adults with hypermobility spectrum disorders and Ehlers-Danlos syndrome: a systematic review.
Hypermobility spectrum disorders (HSD) affect individuals across physical, psychological and social domains, making assessment and management difficult. Management for this condition primarily focuses on addressing the musculoskeletal complaints using physiotherapy rather than the additional manifestations such as fatigue, anxiety and depression. This systematic review aims to identify psychological interventions and assess whether they improve the lived experiences of individuals with HSD. It also aims to assess which psychological interventions were most effective, which symptoms were most effectively managed by a psychological intervention, and whether there were differences between children and adults. Studies were included if they were a randomised controlled trial or pre/post-test design, a sample of any age and clinical diagnosis of HSD (including Ehlers-Danlos syndrome), used a psychological intervention and assessed the effect of the intervention on lived experiences using appropriate outcome measures. Risk of bias was assessed using the Mixed Methods Appraisal Tool. The results were narratively synthesised. Six studies were included in the review, one isolated psychological intervention and five incorporated a psychological intervention within a multidisciplinary programme. The interventions predominantly aimed to reduce pain including intensity, interference, pain-related fear and catastrophising, with anxiety and depression, affect, daily living, fatigue also being evaluated. The most beneficial psychological interventions were those delivered alongside physiotherapy in an outpatient or community setting, improving both the physical and psychological aspects of pain, subsequently improving quality of life. However, there lacks randomised controlled trials with larger samples to definitively confirm the significant findings discussed in this review.


LRRK2 Attenuates Antioxidant Response in Familial Parkinson's Disease Derived Neural Stem Cells.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, characterized by the loss of midbrain dopaminergic neurons which leads to impaired motor and cognitive functions. PD is predominantly an idiopathic disease; however, about 5% of cases are linked to hereditary mutations. The most common mutation in both familial and sporadic PD is the G2019S mutation of leucine-rich repeat kinase 2 (LRRK2). Currently, it is not fully understood how this mutation leads to PD pathology. In this study, we isolated self-renewable, multipotent neural stem cells (NSCs) from induced pluripotent stem cells (iPSCs) harboring the G2019S LRRK2 mutation and compared them with their isogenic gene corrected counterparts using single-cell RNA-sequencing. Unbiased single-cell transcriptomic analysis revealed perturbations in many canonical pathways, specifically NRF2-mediated oxidative stress response, and glutathione redox reactions. Through various functional assays, we observed that G2019S iPSCs and NSCs exhibit increased basal levels of reactive oxygen species (ROS). We demonstrated that mutant cells show significant increase in the expression for KEAP1 and decrease in NRF2 associated with a reduced antioxidant response. The decreased viability of mutant NSCs in the H2O2-induced oxidative stress assay was rescued by two potent antioxidant drugs, PrC-210 at concentrations of 500 µM and 1 mM and Edaravone at concentrations 50 µM and 100 µM. Our data suggest that the hyperactive LRRK2 G2019S kinase activity leads to increase in KEAP1, which binds NRF2 and leads to its degradation, reduction in the antioxidant response, increased ROS, mitochondria dysfunction and cell death observed in the PD phenotype.


Challenges of Data Availability and Use in Conducting Health-EDRM Research in a Post-COVID-19 World.
Disasters disrupt communication channels, infrastructure, and overburden health systems. This creates unique challenges to the functionality of surveillance tools, data collection systems, and information sharing platforms. The WHO Health Emergency and Disaster Risk Management (Health-EDRM) framework highlights the need for appropriate data collection, data interpretation, and data use from individual, community, and global levels. The COVID-19 crisis has evolved the way hazards and risks are viewed. No longer as a linear event but as a protracted hazard, with cascading and compound risks that affect communities facing complex risks such as climate-related disasters or urban growth. The large-scale disruptions of COVID-19 show that disaster data must evolve beyond mortality and frequency of events, in order to encompass the impact on the livelihood of communities, differentiated between population groups. This includes relative economic losses and psychosocial damage. COVID-19 has created a global opportunity to review how the scientific community classifies data, and how comparable indicators are selected to inform evidence-based resilience building and emergency preparedness. A shift into microlevel data, and regional-level information sharing is necessary to tailor community-level interventions for risk mitigation and disaster preparedness. Real-time data sharing, open governance, cross-organisational, and inter-platform collaboration are necessary not just in Health-EDRM and control of biological hazards, but for all natural hazards and man-made disasters.


Clinical characteristics and outcomes of patients with Herpes Zoster Infection in the context of SARS-CoV-2 infection. A case report and a systematic review.
Severe acute respiratory syndrome-coronavirus 2 (SARSCoV2) pandemic has been an unceasing plight with a wide range of clinical presentations. The direct effects of the virus, increased use of medications, and lifestyle changes have contributed to the vulnerability to co-infections. Fungal and bacterial co-infections led to increased morbidity and mortality during the pandemic. Similarly, the surge of skin signs in conjunction with herpes zoster (HZ) manifestations has been reported. In this study, we pooled the data on the clinical characteristics of SARS-CoV-2 patients co-infected with HZ. Electronic databases including PubMed, Scopus, and Google Scholar were extensively searched to identify the relevant studies on HZ infection among the SARS-CoV-2 patients. A total of 79 patients (from case reports, series, and retrospective studies) were included in the analysis. Fever was the most common constitutional symptom recorded, followed by cough and dyspnea. A systemic rash was reported in 78.5% of cases with mild symptoms of HZ and SARS-CoV-2 in 87% and 76%, respectively. Only 19% of the cases presented during the prodrome period of SARS-CoV-2. HZV polymerase chain reaction (PCR) was positive in 8.9% of the cases, and the remaining were diagnosed clinically. SARS-CoV-2 PCR was reported positive in 65 cases (82.3%). Leukopenia was observed in 7 cases (8.9%) and lymphopenia in 25 (31.6%). All patients recovered through conservative treatment. SARS-CoV-2 escalated the incidence of HZ reactivation. Most of the patients were seen with older individuals either simultaneously or a few days after the SARS-CoV-2 infection, but a few cases were reported during the asymptomatic prodrome period of SARS-CoV-2.


Simulation and design of stable channel-guided laser wakefield accelerators.
Most laser wakefield accelerator (LWFA) experiments to date have operated in the self-modulated (SM) regime and have been self-guided. A channel-guided LWFA operating in the standard or resonant regime is expected to offer the possibility of high electron energy gain and high accelerating gradients without the instabilities and poor electron beam quality associated with the SM regime. Plasma channels such as those produced by a capillary discharge have demonstrated guiding of intense laser pulses over distances of several centimeters. Optimizing the performance in a resonant LWFA constrains the on-axis plasma density in the channel to a relatively narrow range. A scaling model is presented that quantifies resonant LFWA performance in terms of the maximum accelerating gradient, dephasing length, and dephasing-limited energy gain. These performance quantities are expressed in terms of laser and channel experimental parameters, clearly illustrating some of the tradeoffs in the choice of parameters. The predicted energy gain in this model is generally lower than that indicated by simpler scaling models. Simulations agree well with the scaling model in both low and high plasma density regimes. Simulations of a channel-guided, self-modulated LWFA are also presented. Compared with the resonant LWFA regime, the requirements on laser and channel parameters in the SM regime are easier to achieve, and a channel-guided SM-LWFA is likely to be less unstable than a self-guided SM-LWFA.


[The use of a digital x-ray diagnostic unit in the obstetrical clinic].
The paper gives account of advantages and disadvantages of ultrasonic and conventional X-ray pelvimetries for diagnosing the contracted pelvis in obstetrics. It also describes a basically new X-ray pelvimetry by using a digital X-ray unit one of whose basic advantages is a low maternal and fetal load (one-twentieth as high as routine X-ray pelvimetry). X-ray pelvimetry with the use of the digital X-ray unit was performed in 366 pregnant and parturient women, of them 188 showed various forms of the anatomically contracted pelvis. Out of them 47% had deliveries by cesarean operation. The potentialities of this unit make it possible to predict both the biomechanism of labor and its outcome.


Health diaries in a rural Australian study.
The authors designed a study around the use of health diaries comprising both open- and closed-ended questions and kept over a 16-week period by 118 rural and remote-dwelling families in Victoria, Australia. Participants documented their use of health services, episodes of illness, actions taken to keep healthy, and reflections on services and programs. In this article, the authors report on the health diary method. They discuss the qualitative ways in which the participants used their study involvement to enrich their lives: accessing health information and advice, furthering their concerns about rural health, and using the research process for social support. The authors discuss issues surrounding the rural and remote context of the study and the length of time over which the diaries were kept.


Rubella cataract in vitro: Sensitive period of the developing human lens.
The clinically known sensitive period of rubella cataract was studied in vitro by infecting 79 human eye rudiments from embryos aged 4-10 wk with rubella virus. The course of the infection was followed by histological and indirect immunofluorescence methods. Of the rudiments, 12 pairs were in the lens placode or open-lens-vesicle stage, 40 already had closed lens vesicles and in another 27 closed-stage pairs an incision was made in the lens capsule before infection to allow the virus to enter the lens. Uninfected controls differentiated well in vitro for 4-6 wk. The eye rudiments infected in the open-lens-vesicle stage showed lens fiber destruction and viral antigens within the lens. No damage or viral antigens were detected in rudiments infected in the closed stage unless the lens capsule was incisedmwhen this was done, however, fiber damage ensued and viral antigens appeared. The lens capsule was concluded to form a protective barrier around the sensirive fibers at the time of closure of the lens vesicle, confirming the earlier hypothesis and clinical findings.


Restoring groundwater quality at the drinking water catchment scale: A multidisciplinary and participatory approach.
Preserving or restoring the quality of groundwater resources with regard to nitrate is a major challenge. To date, useful and easily applicable tools to identify the best measures to implement at local scale are lacking. An innovative methodology is proposed to identify cost-effective restoration measures at the drinking water catchment scale. The methodology is based on the articulation of two tools: a model simulating nitrate groundwater contamination time series and an economic evaluation, within a participatory approach. It was applied to a representative drinking water catchment in Northwest France that has been affected by nitrate contamination for decades. Five scenarios of measures (changes in fertilization and intercropping practices, or in cropping patterns) were co-constructed with stakeholders, evaluated in terms of cost and impact on groundwater nitrate concentration, and discussed with stakeholders. Overall, two scenarios stand out. Introducing hemp in crop rotations is the only scenario generating an economic benefit, but for a very low impact on nitrate concentration (decrease of 4 mg/l by 2050 for 10% of hemp in crop rotations). Introducing alfalfa in crop rotations is the most effective measure to decrease nitrate concentration (decrease of 23 mg/l by 2050 for 20% of alfalfa in crop rotations), and for a moderate cost compared to the other scenarios (25-51 €/ha/year). Results show that substantial changes in cropping patterns - more important than those imagined initially by stakeholders (e.g. converting 40% of cropland to alfalfa) are needed to restore groundwater quality targets in the medium-long term. Measures deemed promising and achievable by the stakeholders proved to be insufficiently effective. The approach developed has been shown to provide valued and trusted information to stakeholders and to objectify debates. Stakeholders have shown interest in the evaluation of costs and further socio-economic information, in addition to the evaluation of the effectiveness of measures on groundwater quality, validating the multidisciplinary dimension of the approach. The approach has the advantage of being easy to implement, and is therefore applicable to other study sites where needed.


Combined tumour of aberrant cytokeratin expressing acral lentiginous melanoma and poroma: Diagnostic challenge.
Combined tumours are uncommon and therefore these tumours may pose a diagnostic challenge. In the current case report, it is aimed to present the clinicopathological features of a combined tumour including melanoma with aberrant cytokeratin expression and poroma.


DNA barcoding unveils a high diversity of caddisflies (Trichoptera) in the Mount Halimun Salak National Park (West Java; Indonesia).
Trichoptera are one of the most diverse groups of freshwater insects worldwide and one of the main bioindicators for freshwater quality. However, in many areas, caddisflies remain understudied due to lack of taxonomic expertise. Meanwhile, globally increasing anthropogenic stress on freshwater streams also threatens Trichoptera diversity. To assess the Trichoptera diversity of the area within and around the Mount Halimun Salak National Park (MHSNP or Taman Nasional Gunung Halimun Salak) in West Java (Indonesia), we conducted a molecular-morphological study on Trichoptera diversity using larvae from a benthic survey and adults from hand-netting. In addition to morphological identification, we applied four different molecular taxon delimitation approaches (Generalized Mixed Yule Coalescent, Bayesian Poisson Tree Processes, Automatic Barcode Gap Discovery and Assemble Species by Automatic Partitioning) based on DNA barcoding of Cytochrome-C-Oxidase I (COI). The molecular delimitation detected 72 to 81 Operational Taxonomic Units (OTU). Only five OTUs could be identified to species level by comparing sequences against the BOLD database using BLAST, and four more to the genus level. Adults and larvae could be successfully associated in 18 cases across six families. The high diversity of Trichoptera in this area highlights their potential as bioindicators for water quality assessment. This study provides an example of how molecular approaches can benefit the exploration of hidden diversity in unexplored areas and can be a valuable tool to link life stages. However, our study also highlights the need to improve DNA barcode reference libraries of Trichoptera for the Oriental region.


Ets21c Governs Tissue Renewal, Stress Tolerance, and Aging in the Drosophila Intestine.
Homeostatic renewal and stress-related tissue regeneration rely on stem cell activity, which drives the replacement of damaged cells to maintain tissue integrity and function. The Jun N-terminal kinase (JNK) signaling pathway has been established as a critical regulator of tissue homeostasis both in intestinal stem cells (ISCs) and mature enterocytes (ECs), while its chronic activation has been linked to tissue degeneration and aging. Here, we show that JNK signaling requires the stress-inducible transcription factor Ets21c to promote tissue renewal in Drosophila. We demonstrate that Ets21c controls ISC proliferation as well as EC apoptosis through distinct sets of target genes that orchestrate cellular behaviors via intrinsic and non-autonomous signaling mechanisms. While its loss appears dispensable for development and prevents epithelial aging, ISCs and ECs demand Ets21c function to mount cellular responses to oxidative stress. Ets21c thus emerges as a vital regulator of proliferative homeostasis in the midgut and a determinant of the adult healthspan.


Tubulobulbar complexes are intercellular podosome-like structures that internalize intact intercellular junctions during epithelial remodeling events in the rat testis.
Tubulobulbar complexes are actin-related double-membrane projections that resemble podosomes in other systems and form at intercellular junctions in the seminiferous epithelium of the mammalian testis. They are proposed to internalize intact junctions during sperm release and during the translocation of spermatocytes through basal junction complexes between neighboring Sertoli cells. In this study we probe apical tubulobulbar complexes in fixed epithelial fragments and fixed frozen sections of rat and mouse testes for junction molecules reported to be present at apical sites of attachment (ectoplasmic specializations) between Sertoli cells and spermatids. The adhesion molecules nectin 2 (PVRL2), nectin 3 (PVRL3) and alpha 6 integrin (ITGA6) are present in the elongate parts of tubulobulbar complexes and concentrated at their distal ends. Tubulobulbar complexes contain cortactin (CTTN), a key component of podosomes, and vesicles at the distal ends of tubulobulbar complexes that contain junction molecules are related to early endosome antigen (EEA1). N-cadherin (CDH2), a protein reported to be present at ectoplasmic specializations, is not localized to these unique junctions or to tubulobulbar complexes but, rather, is primarily concentrated at desmosomes in basal regions of the epithelium. Our results are consistent with the conclusion that tubulobulbar complexes are podosome-like structures that are responsible for internalizing intact intercellular junctions during spermatogenesis.


The NO Dimer.
Spectra of the symmetric nu1 vibration of the NO dimer have been recorded in gas phase at low temperature, with a high-resolution infrared Fourier transform spectrometer. All the lines were least-squares fitted to a Voigt profile convoluted with the well-known apparatus function of the spectrometer. By means of this method, the frequencies of more than 109 new lines were measured. From the intensities of a set of 33 well-fitted and completely isolated lines, the transition moment was extracted. NO-broadening coefficients of the dimer lines were also measured as well as the predissociation time, which was found to be (2.65 +/- 0.53) ns. Copyright 1999 Academic Press.


Green tea catechins and blood pressure: a systematic review and meta-analysis of randomised controlled trials.
Although previous literature has reported that regular green tea consumption may improve blood pressure, the evidence from these studies is not consistent. The present study systematically reviewed randomised controlled trials and examined the effect of green tea consumption on blood pressure using meta-analysis. Search of ProQuest, PubMed, Scopus and Cochrane Library (CENTERAL) was conducted, to identify eligible articles. Articles from 1995 to 2013 were included. A random-effect model was chosen to calculate the effect of combined trials. Thirteen studies were included in the meta-analysis. Green tea consumption significantly changed systolic blood pressure, by -2.08 mm Hg (95% CI -3.06, -1.05), and diastolic blood pressure, by -1.71 mm Hg (95% CI -2.86, -0.56), compared to the control. Changes in lipid profile, blood glucose and body mass index were also assessed in the meta-analysis. A significant reduction was found in total cholesterol (-0.15 mmol/L [95% CI -0.27, -0.02]) and low-density lipoprotein cholesterol (-0.16 mmol/L [95% CI -0.22, -0.09]). Changes in other parameters did not reach statistical significance. Subgroup analysis suggested a greater reduction in both systolic and diastolic blood pressure in studies that included participants with a baseline mean systolic blood pressure of ≥ 130 mm Hg, and studies involving consuming green tea as an extract. The present meta-analysis suggests that green tea and its catechins may improve blood pressure, and the effect may be greater in those with systolic blood pressure ≥ 130 mm Hg. The meta-analysis also suggests that green tea catechins may improve total and low-density lipoprotein cholesterol.


Determinants of pain, disability, health-related quality of life and physical performance in patients with knee osteoarthritis awaiting total joint arthroplasty.
In patients suffering from knee osteoarthritis awaiting knee arthroplasty, to measure associations between several selected determinants and pain, disability, health-related quality of life and physical performance. Validated self-reported measures were collected: (1) Western Ontario and McMaster Universities Osteoarthritis Index, (2) Lower Extremity Functional Scale (LEFS) and (3) Short-Form 36 (SF-36). Physical performance was also assessed with four validated performance tests. Demographic, socioeconomic, psychosocial and clinical characteristics of the participants were also measured. Multivariate regression analyses were used to evaluate potential associations. Higher fear-avoidance beliefs, greater comorbidities, psychological distress and use of a walking aid were significantly associated with worse pain, function or HRQOL (p < 0.05) and explained 12%-35% of the variances of the self-reported measure scores. Pretest pain and change in pain during posttest, greater comorbidities, psychological distress and use of a walking aid were significantly associated with worse performance on the physical tests (p < 0.05) and explained 41%-59% of the variances of the different physical tests results. Several determinants were significantly associated with worse pain, disability, health-related quality of life or physical performance. Several of these associations may be considered clinically important, including psychosocial determinants in relation to self-reported measures, but to physical performance as well. Implications for rehabilitation Knee osteoarthritis is a highly prevalent and disabling condition incurring important socioeconomic costs. Several modifiable determinants have been shown to contribute to pain and disability in individuals suffering from knee OA awaiting TKA. Recent studies demonstrated the efficacy of education and rehabilitation (prehabilitation) in individuals awaiting TKA.


Doping dependence of an n-type cuprate superconductor investigated by angle-resolved photoemission spectroscopy.
We present an angle-resolved photoemission doping dependence study of the n-type cuprate superconductor Nd(2-x)Ce(x)CuO(4+/-delta), from the half-filled Mott insulator to the T(c) = 24 K superconductor. In Nd2CuO4, we reveal the charge-transfer band for the first time. As electrons are doped into the system, this feature's intensity decreases with the concomitant formation of near- E(F) spectral weight. At low doping, the Fermi surface is an electron-pocket (with volume approximately x) centered at (pi,0). Further doping leads to the creation of a new holelike Fermi surface (volume approximately 1+x) centered at (pi,pi). These findings shed light on the Mott gap, its doping evolution, as well as the anomalous transport properties of the n-type cuprates.


[Nuclease S1 for DNA molecular weight determination in multiplasmid Escherichia coli strains].
DNase treatment used to convert supercoiled DNAs to the open form is suitable for molecular weight determination by electron microscopy or agarose gel electrophoresis. The comparative experiments showed that S1-nuclease has advantages over DNase for molecular weight determination in preparations containing many species of plasmids of significantly differing sizes, isolated from multiplasmid E. coli strains.


Influence of the chloride channel of Fusarium oxysporum on extracellular laccase activity and virulence on tomato plants.
CLC-type voltage-gated chloride channels are a family of proteins which mediate chloride transport across the plasma and intracellular membranes. A clc1 gene from the vascular wilt fungus Fusarium oxysporum was characterized and disrupted. The predicted Clc1 protein contained highly conserved transmembrane and CBS domains of this protein family and showed significant identities to the Saccharomyces cerevisiae GEF1 and the Cryptococcus neoformans CLC-A chloride channels. Inactivation of clc1 caused a deficiency in laccase activity which was more severe than that found in any of the structural laccase mutants previously described. The addition of copper sulphate to the growth medium resulted in total recovery of extracellular laccase activity in Deltaclc1 mutants, although it did not activate transcription of any laccase genes. The pleiotropic phenotype displayed by the Fusarium chloride channel-deficient mutants included a significant delay in the development of disease on tomato plants, with a higher sensitivity to oxidative stress compounds as well as a significant decrease in laccase activity, thus suggesting a possible connection between virulence and the two processes. Nevertheless, we cannot rule out that additional phenotypes present in the Deltaclc1 mutants could play an essential role in the full virulence of Fusarium.


Parabolic resection for mitral valve repair.
Parabolic resection, named for the shape of the cut edges of the excised tissue, expands on a common 'trick' used by experienced mitral surgeons to preserve tissue and increase the probability of successful repair. Our objective was to describe and clinically analyze this simple modification of conventional resection. Thirty-six patients with mitral regurgitation underwent valve repair using parabolic resection in combination with other techniques. Institution specific mitral data, Society of Thoracic Surgeons data and preoperative, post-cardiopulmonary bypass (PCPB) and postoperative echocardiography data were collected and analyzed. Preoperative echocardiography demonstrated mitral regurgitation ranging from moderate to severe. PCPB transesophageal echocardiography demonstrated no regurgitation or mild regurgitation in all patients. Thirty-day surgical mortality was 2.8%. Serial echocardiograms demonstrated excellent repair stability. One patient (2.9%) with rheumatic disease progressed to moderate regurgitation 33 months following surgery. Echocardiography on all others demonstrated no or mild regurgitation at a mean follow-up of 22.8+/-12.8 months. No patient required mitral reintervention. Longitudinal analysis demonstrated 80% freedom from cardiac death, reintervention and greater than moderate regurgitation at four years following repair. Parabolic resection is a simple technique that can be very useful during complex mitral reconstruction. Early and intermediate echocardiographic studies demonstrate excellent results.


Thermoelectric detection of spin waves.
We report on the thermoelectric detection of spin waves in Permalloy stripes via the anomalous Nernst effect. Spin waves are locally excited by a dynamic magnetic field generated from a microwave current flowing in a coplanar waveguide placed on top of a Permalloy stripe, which acts as a waveguide for spin waves. Electric contacts at the ends of the Permalloy stripe measure a dc voltage generated along the stripe. Magnetic field sweeps for different applied microwave frequencies reveal, with a remarkable signal-to-noise ratio, an electric voltage signature characteristic of spin-wave excitations. The symmetry of the signal with respect to the applied magnetic field direction indicates that the anomalous Nernst effect is responsible; Seebeck effects, anisotropic magnetoresistance, and voltages due to spin-motive forces are excluded. The dissipation of spin waves causes local heating that drains into the substrate, giving rise to a temperature gradient perpendicular to the sample plane, resulting in the anomalous Nernst voltage.


Demonstrating Pressure Jumping as a Tool to Address the Pressure Gap in High Pressure Photoelectron Spectroscopy of CO and CO2 Hydrogenation on Rh(211).
Operando probing by x-ray photoelectron spectroscopy (XPS) of certain hydrogenation reactions are often limited by the scattering of photoelectrons in the gas phase. This work describes a method designed to partially circumvent this so called pressure gap. By performing a rapid switch from a high pressure (where acquisition is impossible) to a lower pressure we can for a short while probe a "remnant" of the high pressure surface as well as the time dynamics during the re-equilibration to the new pressure. This methodology is demonstrated using the CO2 and the CO hydrogenation reaction over Rh(211). In the CO2 hydrogenation reaction, the remnant surface of a 2 bar pressure shows an adsorbate distribution which favors chemisorbed CHx adsorbates over chemisorbed CO. This contrasts against previous static operando spectra acquired at lower pressures. Furthermore, the pressure jumping method yields a faster acquisition and more detailed spectra than static operando measurements above 1 bar. In the CO hydrogenation reaction, we observe that CHx accumulated faster during the 275 mbar low pressure regime, and different hypotheses are presented regarding this observation.


Acute and chronic changes in diffusivity measures after sports concussion.
Despite negative neuroimaging findings in concussed athletes, studies indicate that the acceleration and deceleration of the brain after concussive impacts result in metabolic and electrophysiological alterations that may be attributable to changes in white matter resulting from biomechanical strain. In the present study we investigated the effects of sports concussion on white matter using three different diffusion tensor imaging (DTI) measures: fractional anisotropy (FA), mean diffusivity (MD), and axial diffusivity (AD). We compared a group of 10 non-concussed athletes with a group of 18 concussed athletes of the same age (mean age 22.5 years) and education (mean 16 years) using a voxel-based approach (VBA) in both the acute and chronic post-injury phases. All concussed athletes were scanned 1-6 days post-concussion and again 6 months later in a 3T Siemens Trio(™) MRI. Three 2×2 repeated-measures analyses of variance (ANOVAs) were conducted, one for each measure of DTI used in the current study. There was a main group effect of FA, which was increased in dorsal regions of both corticospinal tracts (CST) and in the corpus callosum in concussed athletes at both time points. There was a main group effect of AD in the right CST, where concussed athletes showed elevated values relative to controls at both time points. MD values were decreased in concussed athletes, in whom analyses revealed significant group differences in the CST and corpus callosum at both time points. Although the use of VBA does limit the analyses to large tracts, and it has clinical limitations with regard to individual analyses, our results nevertheless indicate that sports concussions do result in changes in diffusivity in the corpus callosum and CST that are not detected using conventional neuroimaging techniques.


A case-control study of stomach cancer in Shandong Province.
Stomach cancer is the leading cause of death from cancer in China. Although the causes of this cancer are unknown, special opportunities exist for the evaluation of etiologic factors in Linqu County in Shandong Province where rates are exceptionally high. We have described here a newly initiated case-control study, which focuses on certain dietary items as risk factors for stomach cancer in Linqu.


RET-familial medullary thyroid carcinoma mutants Y791F and S891A activate a Src/JAK/STAT3 pathway, independent of glial cell line-derived neurotrophic factor.
The RET proto-oncogene encodes a receptor tyrosine kinase whose dysfunction plays a crucial role in the development of several neural crest disorders. Distinct activating RET mutations cause multiple endocrine neoplasia type 2A (MEN2A), type 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC). Despite clear correlations between the mutations found in these cancer syndromes and their phenotypes, the molecular mechanisms connecting the mutated receptor to the different disease phenotypes are far from completely understood. Luciferase reporter assays in combination with immunoprecipitations, and Western and immunohistochemistry analyses were done in order to characterize the signaling properties of two FMTC-associated RET mutations, Y791F and S891A, respectively, both affecting the tyrosine kinase domain of the receptor. We show that these RET-FMTC mutants are monomeric receptors which are autophosphorylated and activated independently of glial cell line-derived neurotrophic factor. Moreover, we show that the dysfunctional signaling properties of these mutants, when compared with wild-type RET, involve constitutive activation of signal transducers and activators of transcription 3 (STAT3). Furthermore, we show that STAT3 activation is mediated by a signaling pathway involving Src, JAK1, and JAK2, differing from STAT3 activation promoted by RET(C634R) which was previously found to be independent of Src and JAKs. Three-dimensional modeling of the RET catalytic domain suggested that the structural changes promoted by the respective amino acids substitutions lead to a more accessible substrate and ATP-binding monomeric conformation. Finally, immunohistochemical analysis of FMTC tumor samples support the in vitro data, because nuclear localized, Y705-phosphorylated STAT3, as well as a high degree of RET expression at the plasma membrane was observed.


One medicine, one university: the DVM/MPH program at the University of Illinois.
The University of Illinois at Urbana-Champaign College of Veterinary Medicine (UIUC-CVM) and the University of Illinois-Chicago School of Public Health (UIC-SPH) are in the fourth year of a collaborative Doctor of Veterinary Medicine and Master of Public Health dual-degree program. The two campuses, one urban and one rural, are 150 miles apart but are sister schools within the University of Illinois system. This article describes the origin of the program, how the program functions across two campuses, its academic focus, required coursework, and research projects designed to fulfill the program's capstone requirements. The article shows how two campuses can be linked through a combination of online and on-site didactic coursework, briefly describes innovative proposals for projects within the United States and abroad, and highlights faculty committed to educating cross-trained public-health professionals while addressing the national need for veterinarians trained in public health. The authors also discuss how the dual-degree program has led to the formation of the Illinois Center for One Medicine, One Health (ICOMOH), an intra-university collaboration focusing on the interface of human, animal, and ecosystem health.


Americans hear as well or better today compared with 40 years ago: hearing threshold levels in the unscreened adult population of the United States, 1959-1962 and 1999-2004.
(1) To present hearing threshold data from a recent nationally representative survey in the United States (National Health and Nutrition Examination Survey, 1999-2004) in a distributional format that might be appropriate to replace Annex B in international (ISO-1999) and national (ANSI S3.44) standards and (2) to compare these recent data with older survey data (National Health Examination Survey I, 1959-1962) on which the current Annex B is based. Better-ear threshold distributions (selected percentiles and their confidence intervals) were estimated using linear interpolation. The 95% confidence intervals for the medians for the two surveys were compared graphically for each of the four age groups and for both men and women. In addition, we calculated odds ratios comparing the prevalences of better-ear hearing impairment (thresholds > 25 dB HL) between the two surveys, for 500, 1000, 2000, and 4000 Hz, and for their four-frequency average. Across age and sex groups, median thresholds were lower (better) in the 1999-2004 survey at 500, 3000, 4000, and 6000 Hz (8000 Hz was not tested in the 1959-1962 survey). For both men and women, the prevalence of hearing impairment was significantly lower in 1999-2004 at 500, 2000, and 4000 Hz, but not at 1000 Hz. For men and women of a specific age, high-frequency hearing thresholds were lower (better) in 1999-2004 than in 1959-1962. The prevalences of hearing impairment were also lower in the recent survey. Differences seen at 500 Hz may be attributable at least in part to changes in standards for ambient noise in audiometry. The National Health and Nutrition Examination Survey 1999-2004 distributions are offered as a possible replacement for Annex B in ISO-1999 and ANSI S3.44.


Rapid Yet Efficient Reduction of Graphene Oxide Triggered by Semi-Molten Metals.
Reduced graphene oxide (rGO) has garnered extensive attention as electrodes, sensors, and membranes, necessitating the efficient reduction of graphene oxide (GO) for optimal performance. In this work, a swift reduction of GO that involves bringing GO foam in contact with semi-molten metals like tin (Sn) and lithium (Li) is presented. These findings reveal that the electrical resistance of GO foam is significantly diminished by its interaction with these metals, even in dry air. Taking inspiration from this technique, Sn foil is employed to encase the GO foam, followed by a calcination in 15 vol% H2 /Ar environment at 235 °C to fabricate the rGO, which demonstrates a remarkably lower electrical resistivity of 0.42 Ω cm when compared to the chemically reduced GO via hydrazine hydrate (650 Ω cm). The reduction mechanism entails the migration of Sn on GO and its subsequent reaction with oxygen functional groups. SnO/Sn(OH)2 formed from the reaction can be subsequently reversed through reduction by H2 to Sn. Utilizing this rGO as the host material for a sulfur cathode, a lithium-sulfur battery is constructed that displays a specific capacity of 1146 mAh g-1 and maintains a capacity retention of 68.4% after 300 cycles at a rate of 0.2 C.


Garcinolic Acid Distinguishes Between GACKIX Domains and Modulates Interaction Networks.
Natural products are often uniquely suited to modulate protein-protein interactions (PPIs) due to their architectural and functional group complexity relative to synthetic molecules. Here we demonstrate that the natural product garcinolic acid allosterically blocks the CBP/p300 KIX PPI network and displays excellent selectivity over related GACKIX motifs. It does so via a strong interaction (KD 1 μM) with a non-canonical binding site containing a structurally dynamic loop in CBP/p300 KIX. Garcinolic acid engages full-length CBP in the context of the proteome and in doing so effectively inhibits KIX-dependent transcription in a leukemia model. As the most potent small-molecule KIX inhibitor yet reported, garcinolic acid represents an important step forward in the therapeutic targeting of CBP/p300.


Current concepts and advances in biomarkers of acute kidney injury.
Despite advancements in standardizing the criteria for acute kidney injury (AKI), its definition remains based on changes in serum creatinine and urinary output that do not specifically represent tubular function or injury and that have significant limitations in the acute hospital setting. Much effort in nephrology has centered on identifying biomarkers of AKI to address these limitations. This review summarizes recent advances in our knowledge of biomarkers involved in pathophysiological processes during AKI and describes their potential clinical implications. Blood and urine biomarkers are released via various mechanisms during renal tubular injury. Urinary kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), insulin-like growth factor-binding protein-7 (IGFBP-7), and tissue inhibitor of metalloprotease-2 (TIMP-2) are released from the proximal tubule while uromodulin (UMOD) is secreted from the loop of Henle and neutrophil gelatinase-associated lipocalin (NGAL) is released from the distal tubule. These biomarkers could therefore be used to localize specific segments of injured tubules. Biomarkers also have diverse roles in pathophysiological processes in AKI, including inflammation, repair, and fibrosis. Current evidence suggests that these biomarkers could be used to predict the transition to chronic kidney disease (CKD), decrease discard of AKI kidneys, differentiate between kidney dysfunction and injury, guide AKI management, and improve diagnosis of diseases such as acute interstitial nephritis (AIN). They could differentiate between disease phenotypes, facilitate the inclusion of a homogenous patient population in future trials of AKI, and shed light on therapeutic pathways to prevent the transition from AKI to CKD. However, a major limitation of current biomarker research in AKI is the lack of tissue correlation. The Kidney Precision Medicine Project, a large-scale national effort, is currently underway to construct a kidney tissue atlas and expand the use of biomarkers to assess nephron health. Numerous biomarkers are involved in distinct pathophysiological processes after kidney injury and have demonstrated potential to improve diagnosis and risk stratification as well as provide a prognosis for patients with AKI. Some biomarkers are ready for use in clinical trials of AKI and could guide management in various clinical settings. Further investigation of these biomarkers will provide insight that can be applied to develop novel therapeutic agents for AKI.


A retractable lid in lecithin:cholesterol acyltransferase provides a structural mechanism for activation by apolipoprotein A-I.
Lecithin:cholesterol acyltransferase (LCAT) plays a key role in reverse cholesterol transport by transferring an acyl group from phosphatidylcholine to cholesterol, promoting the maturation of high-density lipoproteins (HDL) from discoidal to spherical particles. LCAT is activated through an unknown mechanism by apolipoprotein A-I (apoA-I) and other mimetic peptides that form a belt around HDL. Here, we report the crystal structure of LCAT with an extended lid that blocks access to the active site, consistent with an inactive conformation. Residues Thr-123 and Phe-382 in the catalytic domain form a latch-like interaction with hydrophobic residues in the lid. Because these residues are mutated in genetic disease, lid displacement was hypothesized to be an important feature of apoA-I activation. Functional studies of site-directed mutants revealed that loss of latch interactions or the entire lid enhanced activity against soluble ester substrates, and hydrogen-deuterium exchange (HDX) mass spectrometry revealed that the LCAT lid is extremely dynamic in solution. Upon addition of a covalent inhibitor that mimics one of the reaction intermediates, there is an overall decrease in HDX in the lid and adjacent regions of the protein, consistent with ordering. These data suggest a model wherein the active site of LCAT is shielded from soluble substrates by a dynamic lid until it interacts with HDL to allow transesterification to proceed.


Amlodipine/Atorvastatin: a review of its use in the treatment of hypertension and dyslipidaemia and the prevention of cardiovascular disease.
Amlodipine/atorvastatin (Caduet) is a single-tablet, fixed-dose combination of the dihydropyridine calcium channel antagonist amlodipine and the HMG-CoA reductase inhibitor atorvastatin. The bioavailability of amlodipine and atorvastatin with a single-tablet, fixed-dose amlodipine/atorvastatin combination was not significantly different to that with coadministered separate amlodipine and atorvastatin tablets. In well controlled clinical trials in patients with hypertension and dyslipidaemia, once-daily amlodipine and atorvastatin (administered as the single-tablet, fixed-dose combination or coadministered as two separate tablets) effectively reduced systolic BP (SBP) and low-density lipoprotein cholesterol (LDL-C) levels, and enabled more patients to achieve BP and LDL-C goals than single-agent or placebo therapy. There was no modification of the effect of amlodipine on SBP when administered in combination with atorvastatin and there was no modification of the effect of atorvastatin on LDL-C when administered in combination with amlodipine. In noncomparative, titration-to-goal, open-label 'real-world' trials, the single-tablet, fixed-dose combination of amlodipine/atorvastatin enabled patients with hypertension and dyslipidaemia to achieve both BP and LDL-C goals. Administration of a single tablet of amlodipine/atorvastatin, compared with coadministration of these agents as two separate tablets, improved patient adherence, according to a retrospective study that utilized prescription refill rates from a large US insurance database. Data from the large, randomized, double-blind, placebo-controlled ASCOT-LLA trial also demonstrated that the combination of amlodipine-based therapy and atorvastatin was effective in preventing cardiovascular (CV) endpoints in hypertensive patients at risk of CV disease (CVD). In summary, amlodipine/atorvastatin offers a convenient and effective approach to improving adherence and managing CV risk in hypertensive patients with dyslipidaemia or at risk of CVD.


The effect of spaceflight on the gravity-sensing auxin gradient of roots: GFP reporter gene microscopy on orbit.
Our primary aim was to determine whether gravity has a direct role in establishing the auxin-mediated gravity-sensing system in primary roots. Major plant architectures have long been thought to be guided by gravity, including the directional growth of the primary root via auxin gradients that are then disturbed when roots deviate from the vertical as a gravity sensor. However, experiments on the International Space Station (ISS) now allow physical clarity with regard to any assumptions regarding the role of gravity in establishing fundamental root auxin distributions. We examined the spaceflight green fluorescent protein (GFP)-reporter gene expression in roots of transgenic lines of Arabidopsis thaliana: pDR5r::GFP, pTAA1::TAA1-GFP, pSCR::SCR-GFP to monitor auxin and pARR5::GFP to monitor cytokinin. Plants on the ISS were imaged live with the Light Microscopy Module (LMM), and compared with control plants imaged on the ground. Preserved spaceflight and ground control plants were examined post flight with confocal microscopy. Plants on orbit, growing in the absence of any physical reference to the terrestrial gravity vector, displayed typically "vertical" distribution of auxin in the primary root. This confirms that the establishment of the auxin-gradient system, the primary guide for gravity signaling in the root, is gravity independent. The cytokinin distribution in the root tip differs between spaceflight and the ground controls, suggesting spaceflight-induced features of root growth may be cytokinin related. The distribution of auxin in the gravity-sensing portion of the root is not dependent on gravity. Spaceflight appears benign to auxin and its role in the development of the primary root tip, whereas spaceflight may influence cytokinin-associated processes.


Assessing the burden of osteoarthritis in Latin America: a rapid evidence assessment.
This rapid evidence assessment (REA) was conducted to explore the burden of weight-bearing joint osteoarthritis in the developing countries of Latin America. REA methodology used a standardized search strategy to identify observational studies published from 2010 to 23 April 2020 that reported outcomes pertaining to the epidemiology and humanistic or economic burden of weight-bearing osteoarthritis. Relevant data from each included study were used to populate bespoke data extraction tables and qualitatively analyzed. Thirteen publications were identified that reported on knee and hip osteoarthritis in the Latin American region. Overall prevalence of physician-diagnosed symptomatic knee osteoarthritis in adults ranged from 1.55% in Peru to 7.4% in Ecuador. Total prevalence of grade ≥ 2 radiographic knee osteoarthritis was 22% among those ≥ 39 years of age in Brazil and 25.5% among those ≥ 40 years of age in Mexico. The prevalence of symptomatic/radiographic knee osteoarthritis was 7.1% in people ≥ 18 years of age in Mexico and 17.6% among those ≥ 40 years of age. Prevalence of hip osteoarthritis was similar to or slightly lower than knee osteoarthritis. The limited data available indicates weight-bearing osteoarthritis negatively affects quality of life and that the economic burden may vary between countries with different healthcare systems. The limited evidence found in the published literature suggests the burden of osteoarthritis in Latin America is substantial. Our analysis identified several evidence gaps, particularly for health-related quality of life and socioeconomic outcomes. Further research is of particular importance in areas where government-subsidized healthcare and resources are scarce.


Relationship between breastfeeding patterns and intake of vitamin A and iron in children 6-12 months.
The aim of this study was to analyze the association between breastfeeding type in the first six months of life and intake of vitamin A and iron in children 6-12 months of age. It is a cohort study with 226 children. The type of breastfeeding from 1-6 months of life and the food intake from 6 to 12 months were evaluated. Nutrient intake between groups was compared by the Kruskal-Wallis test. The association between nutrient intake and type of breastfeeding was analyzed by Poisson Regression. Consumption below the recommendation of vitamin A and iron was 33.6% and 67.7%, respectively. Infants exclusively and predominantly breastfed from birth to two months had higher vitamin A intake from 6-12 months of life. Infants who were breastfeeding at 6 months had higher vitamin A intake and lower iron by the bivariate analysis. The group that received mixed feeding and artificial feeding at 1 month and the group non-breastfed at 6 months had vitamin A intake below the recommended from 6-12 month of life. The results reinforce the importance of exclusive breastfeeding in the first six months of life contributing to the higher vitamin A intake. Iron intake was lower among breastfed children, but the bioavailability of this nutrient in breast milk is higher.


Transfer of Campylobacter and Salmonella from Poultry Meat onto Poultry Preparation Surfaces.
Thermophilic Campylobacter and Salmonella enterica are major causes of gastrointestinal foodborne infection. Survival of these pathogens on food-associated surfaces is a risk contributing to their spread through the food system. This study examined the transfer of two strains each of C. jejuni, C. coli, Salmonella Enteritidis, and Salmonella Typhimurium from chicken meat to a knife or scissors used on either a plastic or wooden cutting board. Each strain of Campylobacter and Salmonella at ∼108 CFU mL-1 was inoculated (5 mL) onto 25 g of chicken meat with skin and allowed to attach (for 10 min). The meat was then cut (20 times per implement) into 1-cm2 pieces with either a knife or scissors on either a plastic or wooden cutting board. The numbers of pathogens transferred from meat onto cutting implements and cutting board surfaces were enumerated. The surfaces were subsequently either rinsed with water or rinsed with water and wiped with a kitchen towel to mimic commonly used superficial cleaning practices for these implements, and the numbers of pathogens were enumerated again. The bacterial numbers for both pathogens were determined on thin-layer agar. The attachment of the Salmonella strains to chicken meat (∼7.0 to 7.8 log CFU cm-2) was higher than the attachment of the Campylobacter strains (∼4.6 to 6.6 log CFU cm-2). All four Salmonella strains transferred in higher numbers (∼1.9 to 6.3 log CFU cm-2) to all surfaces than did the Campylobacter strains (∼1.1 to 3.9 log CFU cm-2). The transfer rates of both pathogens from the chicken meat to all the surfaces examined varied substantially between ∼0 and 21.1%. The highest rate of transfer (∼21.1%) observed was for C. coli 2875 when transferred from the chicken meat to the scissors. Most cleaning treatments reduced the numbers of both pathogens (∼0.3 to 4.1 log CFU cm-2) transferred to all the surfaces. Our study gives insights into the risks associated with the transfer of Campylobacter and Salmonella from poultry to the surfaces used in poultry preparation.


Laronidase (Aldurazyme): enzyme replacement therapy for mucopolysaccharidosis type I.
Laronidase (Aldurazyme) is a recombinant formulation of alpha-L-iduronidase, the enzyme deficient in mucopolysaccharidosis type I (MPS-I); a disorder associated with skeletal dysplasia, restricted joint movement, short stature, obstructive pulmonary disease, cardiac valvular problems and cognitive impairment (in the severe and intermediate variants). To describe MPS-I and review data on the safety and efficacy of laronidase. Laronidase is safe and effective in stabilizing or improving pulmonary function and physical endurance. As intravenously administered enzyme is unable to correct CNS disease, hematopoietic stem cell transplantation remains the primary treatment for Hurler's syndrome despite the morbidity and mortality risks. Palliative care remains part of the treatment. Long-term studies are required to ascertain the effect of enzyme therapy on survival and its effectiveness in modifying the disease course and reducing morbidity. Intrathecal administration is under investigation for patients with signs of cord compression secondary to glycosaminoglycan accumulation within the dura matter. The cost of therapy remains a concern.


Activation by vanadate of glycolysis in hepatocytes from diabetic rats.
In hepatocytes from starved streptozocin-induced diabetic rats, vanadate increases the glycolytic flux because it raises the levels of fructose-2,6-bisphosphate (Fru-2,6-P2), the main regulatory metabolite of this pathway. This effect of vanadate on Fru-2,6-P2 levels is time and dose dependent, and it remains in cells incubated in a calcium-depleted medium. Vanadate is also able to counteract the decrease on Fru-2,6-P2 levels produced by glucagon, colforsin, or exogenous cAMP. However, vanadate does not modify 6-phosphofructo-2-kinase and pyruvate kinase activities, but it does counteract the inactivation of these enzymes induced by glucagon. Likewise, Fru-2,6-P2ase activity is also not affected by vanadate. In addition, vanadate is able to increase the production of both lactate and CO2 in hepatocytes from streptozocin-induced diabetic rats incubated in the presence of glucose in the medium. Vanadate behaves as a glycolytic effector in these cells, and this effect may be related to its ability to normalize blood glucose levels in diabetic animals.


Cellular and metabolic requirements for induction of macrophage procoagulant activity by murine hepatitis virus strain 3 in vitro.
The cellular basis for the variation in induction of monocyte procoagulant activity (PCA) by murine hepatitis virus strain 3 (MHV-3) was examined using a set of recombinant inbred strains of mice derived from the resistant (A/J) and susceptible C57B1/6J (B) progenitors. Induction of PCA by MHV-3 required live virus and host protein and RNA synthesis. Absolute restriction for induction of PCA was observed at the level of the macrophage. Peritoneal macrophages from resistant parental A/J and RI strains (AXB5) could not be induced to express PCA when stimulated by MHV-3 alone or in the presence of lymphocytes from susceptible and H-2 compatible RI mice (AXB3) although they did respond to endotoxin (LPS). In contrast, macrophages from both susceptible (AXB3) and semisusceptible (AXB1) RI strains of mice expressed a similar increase in PCA after stimulation with MHV-3 in the absence of lymphocytes. The levels of PCA expressed by macrophages in the presence of Thy-1.2+ lymphocytes correlated with susceptibility to disease. Thy-1.2+ lymphocytes from susceptible RI AXB3 mice could induce levels of PCA in macrophages from semisusceptible RI AXB1 mice equivalent to that seen in cultures of macrophages and lymphocytes from susceptible mice. Further subfractionation of Thy-1.2+ cells demonstrated that L3T4+ cells instructed macrophages to produce PCA. Thy-1.2+ cells from MHV-3 immunized resistant AXB5 mice, but not from non-immunized mice, were able to suppress induction of PCA. This suppressor cell activity could be detected 4 days after immunization, reaching maximal activity at day 7 with significant suppression even at 28 days. The PCA was shown to have direct prothrombin cleaving activity (prothrombinase) by ELISA and immunofluorescence staining using the mAb 3D4.3. These results demonstrate that induction of a unique PCA (prothrombinase) is restricted at the level of the macrophage and define a regulatory role for T lymphocytes in its induction.


Intra-abscess administration of antibiotics through ultrasound-guided percutaneous catheter for the treatment of pyogenic liver abscess.
Pyogenic liver abscess is a potentially life-threatening disease. The treatment of a pyogenic liver abscess usually involves ultrasound guided percutaneous drainage because of the poor penetration of the systemic administration of antibiotics inside the abscess. However, a sizable proportion of patients will necessitate surgical interventions, which involves high peri- and post-operative risks. Theoretically, the local instillation of antibiotics inside the pyogenic liver abscess fluid could achieve a high concentration of the antibiotic for a long period of time. This could be especially beneficial for time-dependent bactericidal antibiotics such as beta-lactams, because their bactericidal effectiveness depends on the amount of time that bacteria are exposed to the antibiotic. We are reporting two patients with complicated pyogenic liver abscesses, who were successfully treated with systemic antibiotics and local instillation of meropenem inside the cavities of the abscesses. These cases suggest that the local instillation of the beta-lactam antibiotics could be an effective and a safe strategy for the treatment of pyogenic liver abscesses that cannot be completely drained through an ultrasound guided percutaneous catheter.


Genomic expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease.
To evaluate global genome expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease (DMVD). Anterior mitral valve leaflets of 4 dogs with severe DMVD and 4 healthy control dogs. Transcriptional activities of 23,851 canine DNA sequences were determined by use of an oligonucleotide microarray. Genome expression patterns of tissue from dogs with DMVD were evaluated by measuring the relative amount of complementary RNA hybridization to the microarray probes and by comparing it with gene expression from healthy control dogs. 229 transcripts were differentially expressed (>or= 2-fold change). In dogs with DMVD, expression of 159 transcripts was upregulated and expression of 70 transcripts was downregulated. Of the 229 transcripts, 152 genes could be specifically identified. These genes were grouped into 1 of 9 categories on the basis of their primary physiologic function. Grouping revealed that pathways involving cell signaling, inflammation, extracellular matrix, immune function, cell defense, and metabolism were generally upregulated. Inflammatory cytokines and the serotonin-transforming growth factor-beta pathway were identified as contributory to the pathophysiologic aspects of DMVD. Evaluation of global expression patterns provides a molecular portrait of mitral valve disease, yields insight into the pathophysiologic aspects of DMVD, and identifies intriguing genes and pathways for further study.


Application of the "hybrid approach" to chronic total occlusion interventions: a detailed procedural analysis.
To assess the outcomes of the "hybrid" approach to chronic total occlusion (CTO) percutaneous coronary interventions (PCIs). The "hybrid approach" to CTO PCI advocates appropriate and early change of crossing strategy to maximize success, safety, and efficiency. We prospectively recorded and analyzed detailed step-by-step procedural data in 73 consecutive CTO PCI cases performed by a single operator between July 2011 and August 2012. Technical success was achieved in 66 of 73 cases (90.4%). Mean patient age was 65 ± 7 years, and 30% had prior coronary artery bypass surgery. Dual injection was used in 78%. The primary approach was retrograde in 9 cases (12.5%) and antegrade in 64 cases (87.5%), of whom 25 cases (39.1%) underwent retrograde attempt after failed antegrade approach. The initial crossing approach was successful in 40 cases (54.8%), but 32 cases (44%) required 3.6 ± 1.4 approach changes (range 2-7). Antegrade wire escalation, antegrade dissection/reentry, and retrograde crossing were utilized in 97.2%, 46.6%, and 46.6% of cases, respectively. Among successful cases, the final CTO crossing technique was antegrade wire escalation in 50.0%, antegrade dissection/reentry in 24.2%, and retrograde in 25.8%. The mean procedure time, fluoroscopy time, and air kerma radiation exposure until CTO crossing or stopping the procedure were 66 ± 55 minutes, 25 ± 23 minutes, and 2.3 ± 1.9 Gray, respectively. Three patients (4.1%) had a major complication. In the "hybrid approach" to CTO PCI, changes in crossing strategy were needed in approximately half the cases, resulting in high success and low complication rates.


Mortality associated with ingestion of sea urchins in loggerhead sea turtles (Caretta caretta): A case series.
The aims of this study were: a) to describe the pathological and laboratory findings in a case series of stranding and mortality associated with ingestion of large amounts of sea urchins in loggerhead turtles (Caretta caretta), and b) to alert veterinarians and biologists involved in sea turtle conservation of this cause of stranding and/or death. The six loggerheads studied were stranded on the coasts of Gran Canaria, Canary Islands, Spain, between 2008 and 2015. Post mortem studies included pathological, microbiological, and sea urchin species identification procedures. All turtles showed severe intestinal impaction caused by large amounts of sea urchins, mainly affecting the colon and the caudal half of the small intestine. Histologically, severe focal fibrinonecrotic enteritis was diagnosed in two turtles. In the remaining turtles, lesions ranged from mild desquamation of the intestinal epithelium to severe congestion of the blood vessels of lamina propria, submucosa, muscular and serosa, and edema. Vibrio sp. was isolated from the spleen and intestinal mucosa of a loggerhead in which focal fibrinonecrotic enteritis had been diagnosed. In five turtles, all the remains were fragments from long-spined sea urchins (Diadema africanum); the last turtle contained a mixture of long-spined sea urchin (90%) and purple sea urchin (Sphaerechinus granularis) (10%) remains. Although the prevalence of this cause of stranding was low (< 1.6%) compared to other mortality causes, continued overfishing and anthropogenic climate change could increase its incidence. Intestinal impaction with large amounts of sea urchins should be included in the differential diagnosis of gastrointestinal diseases in sea turtles, and the possible toxic effect of some sea urchin species on sea turtles should also be investigated.


A rude awakening: post-take ward round in the department of medicine for the elderly.
This paper describes the post-take ward round of a department of medicine for the elderly (DME), to portray the nature of the medical admissions and their immediate management. The data concern the patients seen by one consultant in 28 such ward rounds during the last four months of 1997, in a teaching hospital where the DME is separate from the department of general internal medicine. 254 patients were seen, 107 men and 147 women, with an average age of 82.4 years (range 73-102). The decisions taken included diagnosis, further investigations, treatment, referral, discharge, and resuscitation status. Very few admissions were judged inappropriate, particularly among the majority referred by general practitioners. 101 patients were thought suitable for transfer to the department of general internal medicine, 109 definitely unsuitable. These findings support the view that, if medical beds are to be freed, the initiative must come from facilitating discharge rather than curtailing admission. Generalists are needed to sort and manage these patients. In the UK, these will often be general internal medicine consultant geriatricians, while the younger patients are seen by consultants practising general internal medicine in addition to one of the specialties. Sizeable numbers of these consultants are needed if the post-take ward round is to be efficient and not conflict with their fixed commitments.


Survival in a coronary care unit.
The mortality among 253 patients with definite, acute myocardial infarction admitted to the coronary care unit (CCU) of the New Orleans VA Hospital during a two-year period is reported. Thirty-one (12.3%) of these patients died in the CCU. Five others died on the medical wards after release from the CCU. A total of 217 patients was discharged in good condition from the hospital after a minimal stay of three to four weeks, resulting in a survival rate of 85.8%.


Chromium-manganese selenide carbonyl complexes: paramagnetic clusters and relevance to C=O activation of acetone.
The paramagnetic even-electron cluster, [Et(4)N](2)[Se(2)Cr(3)(CO)(10)], was found to react readily with Mn(CO)(5)Br in acetone to produce two unprecedented mixed chromium-manganese selenide carbonyl complexes, [Et(4)N][Me(2)CSe(2){Mn(CO)(4)}{Cr(CO)(5)}(2)] ([Et(4)N][1]) and [Et(4)N](2)[Se(2)Mn(3)(CO)(10){Cr(CO)(5)}(2)] ([Et(4)N](2)[2]). X-ray crystallographic analysis showed that anion 1 consisted of two Se-Cr(CO)(5) moieties, which were further bridged by one isopropylene group and one Mn(CO)(4) moiety. The dianionic cluster 2 was shown to display a Se(2)Mn(3) square-pyramidal core with each Se atom externally coordinated by one Cr(CO)(5) group. The formation of complex 1, presumably via C=O activation of acetone, was further facilitated by acidification of the reaction of [Et(4)N](2)[Se(2)Cr(3)(CO)(10)] with Mn(CO)(5)Br in acetone. Complex 1 readily transformed into 2 upon treatment with Mn(2)(CO)(10) in a KOH/MeOH/MeCN solution. Cluster 2 was a 51-electron species, which readily converted to the known 49-electron cluster [Se(2)Mn(3)(CO)(9)](2-) upon heating and bubbling with CO. Magnetic studies of the even-electron cluster, [Et(4)N](2)[Se(2)Cr(3)(CO)(10)], and the odd-electron species, [Et(4)N](2)[2] and [PPN](2)[Se(2)Mn(3)(CO)(9)], were determined by the SQUID measurement to have 2, 3, and 1 unpaired electrons, respectively. In addition, the nature and formation of complexes 1 and 2 are discussed, and the magnetic properties and electrochemistry of [Se(2)Cr(3)(CO)(10)](2-), 2, and [Se(2)Mn(3)(CO)(9)](2-) were further studied and elucidated by molecular orbital calculations at the PW91 level of density functional theory.


Bifunctional Oxygen Electrocatalysis on Mixed Metal Phthalocyanine-Modified Carbon Nanotubes Prepared via Pyrolysis.
Non-precious-metal catalysts are promising alternatives for Pt-based cathode materials in low-temperature fuel cells, which is of great environmental importance. Here, we have investigated the bifunctional electrocatalytic activity toward the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER) of mixed metal (FeNi; FeMn; FeCo) phthalocyanine-modified multiwalled carbon nanotubes (MWCNTs) prepared by a simple pyrolysis method. Among the bimetallic catalysts containing nitrogen derived from corresponding metal phthalocyanines, we report the excellent ORR activity of FeCoN-MWCNT and FeMnN-MWCNT catalysts with the ORR onset potential of 0.93 V and FeNiN-MWCNT catalyst for the OER having EOER = 1.58 V at 10 mA cm-2. The surface morphology, structure, and elemental composition of the prepared catalysts were examined with scanning electron microscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The FeCoN-MWCNT and FeMnN-MWCNT catalysts were prepared as cathodes and tested in anion-exchange membrane fuel cells (AEMFCs). Both catalysts displayed remarkable AEMFC performance with a peak power density as high as 692 mW cm-2 for FeCoN-MWCNT.


Tamoxifen blocks estrogen-induced B cell maturation but not survival.
Estrogen treatment has been shown not only to exacerbate disease activity and accelerate death in spontaneous murine models of lupus but also to induce a lupus-like phenotype in non-spontaneously autoimmune mice. In mice transgenic for the H chain of an anti-DNA Ab, estrogen rescues naive autoreactive B cells that normally are deleted and causes them to mature to a marginal zone phenotype. Estrogen further leads to the activation of this population causing an elevation of serum anti-DNA Ab titers and renal disease. This study was designed to evaluate the therapeutic potential of tamoxifen, a selective estrogen receptor modulator, on estrogen-induced lupus. Mice treated with both estradiol and tamoxifen showed no elevation in anti-DNA Ab titers and consequently no glomerular IgG. The DNA-reactive B cell population that is rescued by estrogen was present in an anergic state in mice treated with both estradiol and tamoxifen. Estradiol enhances transitional B cell resistance to apoptosis and expands the population of marginal zone B cells; tamoxifen did not impede the enhanced resistance to apoptosis, but prevented the development of autoreactive cells as marginal zone B cells. Thus, estrogen-induced autoimmunity proceeds through two distinct molecular pathways, one affecting survival and the other maturation. Activation, but not survival, of autoreactive B cells can be abrogated by tamoxifen. Drugs that modulate even some of the effects of estrogen may be beneficial in patients with lupus. Eventually, understanding the pathways involved in survival and activation of autoreactive B cells will permit the development of therapeutics that target all relevant pathways.


Discordant growth hormone and IGF-1 levels post pituitary surgery in patients with acromegaly naïve to medical therapy and radiation: what to follow, GH or IGF-1 values?
New criteria that define acromegaly remission are more stringent: normal (age/sex-adjusted) insulin-like growth factor type 1 (IGF-1), growth hormone (GH) random (GHr) <1 μg/L, and a GH nadir (GHn) during oral glucose tolerance test (OGTT) of <0.4 μg/L. Discordance between GH and IGF-1 values is often attributed to somatostatin receptor ligands (SRLs) or radiation. The purpose of this study was to evaluate rates of discordant IGF-1 and GH levels in patients with GH secreting adenomas (after pituitary surgery), who were naïve to any other treatment. We retrospectively analyzed data over a 5 year time period (2006-2010), in post-surgery acromegaly patients who had elevated IGF-1 but normal GH levels (per the new cure criteria). Symptoms of acromegaly were scored according to a 4-point scale. Fifty-four patients had post-operative GHr and IGF-1 measurements, 28 patients had GHn during OGTT, and 16 patients had 5-point 2-h GH day curve tests. Thirteen of 54 (24%) patients were found to have intermittent persistent discordant values; high IGF-1 and normal GH at final evaluation (77% of these patients were women). Patients had a median number of IGF-1 evaluations of 7.5 (range: 2-15) over a median of 22 months (range: 3-47 months). Mean elevated IGF-1 in the discordant population was 1.25 × upper limit of normal (ULN) ± 0.17 (range: 1.01-1.6 × ULN). Twelve of the 13 (92%) patients had macroadenomas; 10 of the 13 (69%) patients had mammosomatotroph, mixed lacto/somatotroph tumors or prolactin staining. No patient in the discordant population was on estrogen replacement therapy or had overt cardiac disease. When the relatively asymptomatic discordant population was compared with 35 patients from the concordant population (six were excluded because of preoperative medical treatment for acromegaly), no significant difference between age, gender distribution, body mass index (BMI), presence of diabetes mellitus (DM) or glucose intolerance and adrenal insufficiency between groups was noted. In our study of postoperative patients with acromegaly naïve to both SRLs and radiation, using new GH cut-off levels, 24% had intermittent or persistent discordant values. Our results highlight that relying on IGF-1 or GH measurements alone is not adequate for assessing disease control in surgically treated acromegaly patients. Management of such patients needs to be individualized and long-term studies evaluating morbidity and mortality incorporated into treatment decisions. Further studies with larger patient populations and longer follow-up are required to determine the long-term implications of discordant GH and IGF-1 value patterns.


Expression of sodium channel α subunits 1.1, 1.2 and 1.6 in rat hippocampus after kainic acid-induced epilepsy.
Voltage-gated Na(+) channels control neuronal excitability and are the primary target for the majority of anti-epileptic drugs. This study investigates the (sub)cellular expression patterns of three important brain-associated Na(+) channel α subunits: NaV1.1, NaV1.2 and NaV1.6 during epileptogenesis (induced by kainic acid) using time points that cover the period from induction to the chronic phase of epilepsy. NaV1.1 immunoreactivity was persistently reduced at 1 day, 3 weeks and 2 months after SE in CA1 and CA3. About 50% of the NaV1.1-positive interneurons was lost at one day after SE in all regions investigated. In the hilus a similar reduction in NeuN-positive neurons was found, while in the CA1 and CA3 region the loss in NeuN-positive neurons only reached 15% in the chronic phase of epilepsy. This implies a stronger shift in the balance between excitation and inhibition toward excitation in the CA1 and CA3 region than in the hilus. NaV1.2 immunoreactivity in the inner molecular layer of the dentate gyrus was lower than control at 1 day after SE. It increased at 3 weeks and 2 months after SE in the inner molecular layer and overlapped with sprouted mossy fibers. NaV1.6 immunoreactivity in the dendritic region of CA1 and CA3 was persistently reduced at all time-points during epileptogenesis. Some astrocytes expressed NaV1.1 and NaV1.6 at 3 weeks after SE. Expression data alone are not sufficient to explain changes in network stability, or infer causality in epileptogenesis. These results demonstrate that hippocampal sub-regional expression of NaV1.1, NaV1.2 and NaV1.6 Na(+) channel α subunits is altered during epileptogenesis in a time and location specific way. This implies that understanding epileptogenesis has to take into account several distinct and type-specific changes in sodium channel expression.


Is infertility a disease and does it matter?
Claims about whether or not infertility is a disease are sometimes invoked to defend or criticize the provision of state-funded treatment for infertility. In this paper, I suggest that this strategy is problematic. By exploring infertility through key approaches to disease in the philosophy of medicine, I show that there are deep theoretical disagreements regarding what subtypes of infertility qualify as diseases. Given that infertility's disease status remains unclear, one cannot uncontroversially justify or undermine its claim to medical treatment by claiming that it is or is not a disease. Instead of focusing on disease status, a preferable strategy to approach the debate about state-funded treatment is to explicitly address the specific ethical considerations raised by infertility. I show how this alternative strategy can be supported by a recent theoretical framework in the philosophy of medicine which avoids the problems associated with the concepts of health and disease.


Panniculitis: an unusual cutaneous manifestation of rheumatoid arthritis.
Specific and nonspecific panniculitis may occur during the course of connective tissue diseases. However, association of panniculitis and rheumatoid arthritis has only rarely been described, and with so few reports, it is difficult to know the significance of this unusual association. We describe 2 patients with rheumatoid arthritis and features of Sjögren syndrome in whom panniculitis developed during the course of the disease. Histologic confirmation of septal panniculitis was established in one case and the panniculitis in this case improved as the arthritis resolved.


Efficiency and ecological safety of herbicide haloxyfop-R-methyl on removal of coastal invasive plant Spartina alterniflora.
Spartina alterniflora is a global invasive plant and has caused considerable damage to coastal wetland ecosystem. This study evaluated the efficiency and ecological safety of herbicide haloxyfop-R-methyl (HPME) in removing S alterniflora in Laizhou Bay. The results showed that the density of regenerated S. alterniflora after 10 months of application of 0.01, 0.02 and 0.03 g/m2 HPME decreased by 86.67 %, 99.16 % and 99.31 %, respectively. Moreover, seed abortion rates were 62.25 %, 92.24 % and 94.82 %, and weight of roots in HPME groups were 56.63 %, 59.99 %, and 40.10 % of those in the control group. After 4 days of application, HPME could not be detected in S. alterniflora and sediments. In addition, HPME did not change sediment physicochemical properties, macrozoobenthos community and microbial community structure during 16 days, but increased the density of native macrozoobenthos after 1 year. Therefore, HPME might be an effective and ecologically safe chemical for the eradication of S. alterniflora.