Prognostic stratification based on the levels of tumor-infiltrating myeloid-derived suppressor cells and PD-1/PD-L1 axis in locally advanced rectal cancer.
Although rectal cancer remains somewhat sanctuary to the contemporary immunotherapy, there is increasing knowledge on clinical implications of anti-tumor immunity. This study evaluated the prognostic relevance of two immune-inhibitory functions, myeloid-derived suppressor cells (MDSCs) and programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis. Study cohort is comprised of 165 patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy followed by definitive resection. Using postsurgical tissue microarrays, the number of MDSCs, PD-1+/CD8+ tumor-infiltrating lymphocyte (TIL) ratio, and PD-L1 expression scores in stromal immune cells and tumor cells were assessed. Positive correlation was observed between the PD-1+/CD8+ TIL ratio and number of MDSCs (P < 0.001). The greater the immune infiltrates, the higher the PD-L1 immune cell score (P < 0.001). MDSCHigh, PD-1+/CD8+ TILHigh, PD-L1 immune cell scoreLow, and PD-L1 tumor H-scoreHigh were associated with worse disease-free survival (DFS) (P < 0.001, P = 0.042, 0.047, and P < 0.001, respectively). To integrate the adverse effects of MDSCHigh, PD-1+/CD8+ TILHigh, and either PD-L1 immune cell scoreLow (set I) or tumor H-scoreHigh (set II), prognostic risks were stratified according to the number of factors: 0, 1, and 2-3 (P < 0.001 for I and II). On multivariate analyses, patients with multiple risk factors for set I and II had worse prognosis (P < 0.001; 2-3 vs. 0 for models I and II), and the two prognostic models had acceptable predictability. In this study, integration of the prognostic impact of MDSCs and PD-1/PD-L1 stratified the long-term risks of patients with locally advanced rectal cancer. Thus, further exploration could be focused to the identified subset of patients carrying worse prognosis, where potential benefits could be derived by targeting the two components contributing to the immunosuppressive microenvironment.


Evolution of isoprenyl diphosphate synthase-like terpene synthases in fungi.
Terpene synthases (TPSs) and trans-isoprenyl diphosphate synthases (IDSs) are among the core enzymes for creating the enormous diversity of terpenoids. Despite having no sequence homology, TPSs and IDSs share a conserved "α terpenoid synthase fold" and a trinuclear metal cluster for catalysis, implying a common ancestry with TPSs hypothesized to evolve from IDSs anciently. Here we report on the identification and functional characterization of novel IDS-like TPSs (ILTPSs) in fungi that evolved from IDS relatively recently, indicating recurrent evolution of TPSs from IDSs. Through large-scale bioinformatic analyses of fungal IDSs, putative ILTPSs that belong to the geranylgeranyl diphosphate synthase (GGDPS) family of IDSs were identified in three species of Melampsora. Among the GGDPS family of the two Melampsora species experimentally characterized, one enzyme was verified to be bona fide GGDPS and all others were demonstrated to function as TPSs. Melampsora ILTPSs displayed kinetic parameters similar to those of classic TPSs. Key residues underlying the determination of GGDPS versus ILTPS activity and functional divergence of ILTPSs were identified. Phylogenetic analysis implies a recent origination of these ILTPSs from a GGDPS progenitor in fungi, after the split of Melampsora from other genera within the class of Pucciniomycetes. For the poplar leaf rust fungus Melampsora larici-populina, the transcripts of its ILTPS genes were detected in infected poplar leaves, suggesting possible involvement of these recently evolved ILTPS genes in the infection process. This study reveals the recurrent evolution of TPSs from IDSs since their ancient occurrence and points to the possibility of a wide distribution of ILTPS genes in three domains of life.


Identification and functional analysis of two new de novo KCNMA1 variants associated with Liang-Wang syndrome.
Loss-of-function KCNMA1 variants cause Liang-Wang syndrome (MIM #618729), a newly identified multiple malformation syndrome with a broad spectrum of developmental and neurological phenotypes. However, the full spectrum of clinical features and underlying pathogenic mechanisms need full elucidation. Exome sequencing was used to identify pathogenic variants. Patch-clamp recordings were performed to access the effects of KCNMA1 variants on BK channels. Total and membrane protein expression levels of BK channels were characterized using Western blotting. We report identification and functional characterization of two new de novo loss-of-function KCNMA1 variants p.(A172T) and p.(A314T) with characteristics of Liang-Wang syndrome. Variant p.(A172T) is associated with developmental delay, cognitive impairment and ataxia. Mechanistically, p.(A172T) abolishes BK potassium current, inhibits Mg2+ -dependent gating, but shifts conductance-voltage (G-V) curves to more positive potentials when complexed with WT channels. Variant p.(A314T) is associated with developmental delay, intellectual disability, cognitive impairment, mild ataxia and generalized epilepsy; suppresses BK current amplitude; and shifts G-V curves to more positive potentials when expressed with WT channels. In addition, two new patients with previously reported gain-of-function variants p.(N536H) and p.(N995S) are found to show epilepsy and paroxysmal dyskinesia as reported previously, but also exhibit additional symptoms of cognitive impairment and dysmorphic features. Furthermore, variants p.(A314T) and p.(N536H) reduced total and membrane levels of BK proteins. Our findings identified two new loss-of-function mutations of KCNMA1 associated with Liang-Wang syndrome, expanded the spectrum of clinical features associated with gain-of-function KCNMA1 variants and emphasized the overlapping features shared by gain-of-function and loss-of-function mutations.


A Descriptive Study of Keel Bone Fractures in Hens and Roosters from Four Non-Commercial Laying Breeds Housed in Furnished Cages.
The presence of keel bone fractures (KBF) in laying hens has been documented and discussed by several authors, nevertheless the causative factors behind KBF remain uncertain. High prevalence of KBF have been reported in all commercial egg production systems, in different genetic lines and at different ages. Several of the proposed causal mechanisms behind KBF are linked to selection for efficient production. It is, therefore, of interest to explore whether less selected breeds have a lower occurrence of keel bone fractures compared to reports from highly selected, modern laying hen breeds. Thus, the aim of the current study was to investigate keel bones of hens from four non-commercial layer breeds. Birds were housed in furnished cages and keel bones examined at 30 and 63 weeks of age, using a portable X-ray equipment. The results from this descriptive study indicate a low prevalence of KBF at both ages in all four breeds, with only five KBF detected in 213 X-ray pictures taken from 126 birds. Of these, four of the KBF were observed in the most genetically selected breed, with an early onset of lay. None of the roosters examined exhibited KBF. The overall low numbers of KBF found indicate that genetic factors may be involved in KBF and, thus that selective breeding may help to reduce the susceptibility to KBF. Finally, this study highlights the importance of poultry conservation to secure genetic diversity, which may be an important resource in future selection schemes.


Synthesis of Enantiomerically Pure N-Boc-Protected 1,2,3-Triaminopropylphosphonates and 1,2-Diamino-3-Hydroxypropylphosphonates.
All possible isomers of 1,2,3-tri(N-tert-butoxycarbonylamino)propylphosphonate 6 were synthesized from the respective diethyl [N-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates 5 via opening the aziridine ring with trimethylsilyl azide (TMSN3) followed by hydrogenolysis in the presence of di-tert-butyl dicarbonate (Boc2O). [N-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates (1R,2R,1'S)-5a and (1S,2S,1'R)-5c were smoothly transformed into diethyl 3-acetoxy-1-benzylamino-2-[N-(1-phenylethyl)amino]propylphosphonates (1R,2R,1'S)-9a and (1S,2S,1'R)-9c, respectively by the opening of the aziridine ring with acetic acid. Transformations of [N-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates (1S,2R,1'S)-5b and (1R,2S,1'R)-5d into diethyl 3-acetoxy-1-benzylamino-2-[(1-phenylethyl)amino]propylphosphonates (1S,2R,1'S)-9b and (1R,2S,1'R)-9d were accompanied by the formation of ethyl {1-(N-benzylacetamido)-3-hydroxy-2-[(1-phenylethyl)amino]propyl}phosphonate (1S,2R,1'S)-10b and (1R,2S,1'R)-10d and 3-(N-benzylacetamido)-4-[N-(1-phenylethyl)]amino-1,2-oxaphospholane (3S,4R,1'S)-11b and (3R,4S,1'R)-11d as side products. Diethyl (1R,2R)-, (1S,2S)-, (1S,2R)- and (1R,2S)-3-acetoxy-1,2-di(N-tert-butoxycarbonylamino)propylphosphonates 7a-7d were obtained from the respective 3-acetoxy-1-benzylamino-2-[N-(1-phenylethyl)amino]propylphosphonates 9a-9d by hydrogenolysis in the presence of Boc2O.


MRI indirect stereotactic targeting for deep brain stimulation in Parkinson's disease.
Stereotactic localisation of brain targets for functional neurosurgery might be obtained with different neuroimaging sources. Magnetic resonance (MR) might be of particular interest for its high definition of the various brain structures; unfortunately, magnetic field distortion and inaccuracy in imaging reproduction constrain the use of MRI in stereotactic surgery. We present an experimental work devoted to the utilization of MRI in the targeting of the subthalamic nucleus for deep brain stimulation (DBS) in Parkinsonian patients. Experimental data were obtained after PVC phantom and fixed human brain measurements of the stereotactic coordinates of specific basal ganglia structures. Intrinsic and external sources of error and imaging distortion have been carefully corrected. Afterwards, 36 patients, operated for DBS in the subthalamus for Parkinson's disease (PD), have been investigated. MRI targeting proved to be clinically successful; comparing anatomical and neurophysiological findings, MRI targeting scattered from the neurophysiological targeting in a minority of cases. MRI targeting proved to be reliable for functional stereotactic surgery, pending careful and adequate quality control of the distortion and of the sources of error.


Effects of urinary crystals induced by acetazolamide, uracil, and diethylene glycol on urinary bladder carcinogenesis in N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated rats.
In order to examine the promoting effect of urinary crystals on urinary bladder carcinogenesis, acetazolamide, uracil, and diethylene glycol, all of which have been reported to cause urinary crystals or calculi, were administered to male F344 rats for 32 weeks after pretreatment with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks. A marked increase in urinary crystals was observed in acetazolamide-treated rats and a slight increase in crystals was observed in uracil- and diethylene glycol-treated rats. Histological examination of the urinary bladder revealed that the BBN-acetazolamide treatment resulted in a higher incidence of carcinoma than BBN-control. Uracil and diethylene glycol did not cause any significant difference compared to the control. Promoting effects by urinary crystals were not clearly shown in the present experiment and, therefore, urinary crystals appear to play a very limited role, if any, in urinary bladder carcinogenesis.


Crystal structures of a group II intron lariat primed for reverse splicing.
The 2'-5' branch of nuclear premessenger introns is believed to have been inherited from self-splicing group II introns, which are retrotransposons of bacterial origin. Our crystal structures at 3.4 and 3.5 angstrom of an excised group II intron in branched ("lariat") form show that the 2'-5' branch organizes a network of active-site tertiary interactions that position the intron terminal 3'-hydroxyl group into a configuration poised to initiate reverse splicing, the first step in retrotransposition. Moreover, the branchpoint and flanking helices must undergo a base-pairing switch after branch formation. A group II-based model of the active site of the nuclear splicing machinery (the spliceosome) is proposed. The crucial role of the lariat conformation in active-site assembly and catalysis explains its prevalence in modern splicing.


Cardiac fibroblast death by ischemia/reperfusion is partially inhibited by IGF-1 through both PI3K/Akt and MEK-ERK pathways.
Cardiac fibroblast (CF) death by ischemia/reperfusion (I/R) has major implications for cardiac wound healing. Although IGF-1 has well-known cytoprotective effects, no study has been done on CF subjected to simulated I/R. Simulated ischemia of neonate rat CF was performed in a free oxygen chamber in an ischemic medium; reperfusion was done in normal culture conditions. Cell viability was evaluated by trypan blue assay, and apoptosis by a FACS flow cytometer; p-ERK-1/2 and p-Akt levels were determined by western blot. We showed that simulated I/R triggers CF death by necrosis and apoptosis. IGF-1 partially inhibits I/R-induced apoptosis. PD98059 and LY294002 neutralize the preventive effects of IGF-1. IGF-1 partially inhibits CF apoptosis induced by simulated I/R by PI3K/Akt- and MEK/ERK1/2-dependent signaling pathways.


Medical management of cerebral metastases.
Brain edema, seizures, and venous thromboembolism are frequently encountered complications of cerebral metastases that result in increased morbidity and mortality. Effective medical management of these complications with steroids, anticonvulsants, and anticoagulants can result in symptomatic improvement and a better quality of life for these patients. However, these medical therapies should be administered only when indicated as each is associated with potentially serious toxicity.


Release of cytochrome c into the extracellular space contributes to neuronal apoptosis induced by staurosporine.
The mitochondrial protein cytochrome c has been identified as one of the key signalling molecules of apoptosis. In the present study, we used primary neuronal cultures to investigate whether cytochrome c was released from the mitochondria into the cytosol and subsequently into the culture medium during staurosporine-induced apoptosis and whether extracellular cytochrome c modulates the degree of damage caused by staurosporine. We found the cytochrome c content in the mitochondria decreased 24 h after and increased in the cytosol 8 h after staurosporine was added to the culture medium. The cytochrome c content of the culture medium increased from 8 h up to 24 h after starting the staurosporine treatment. In parallel with the release of cytochrome c into the culture medium, membrane leakage occurred as determined by the release of LDH. Addition of cytochrome c accelerated, whereas the addition of anti-cytochrome c antibodies reduced staurosporine-induced neuronal death suggesting a pro-apoptotic role of cytochrome c released into the culture medium. Under control conditions, extracellularly added cytochrome c (25 ng/ml), which was in the range of the amount of cytochrome c released from staurosporine-treated neurons into the culture medium, increased the percentage of apoptotic neurons to 30% compared with 18% in vehicle-treated controls. Our results suggest that the release of cytochrome c into the extracellular space contributes to neuronal apoptosis induced by staurosporine.


Evidence that the reactions of cadmium in the presence of metallothionein can produce hydroxyl radicals.
A variety of Cu reconstituted metallothioneins (MTs) containing different amounts of copper ions together with Cd7-MT free of copper were prepared and used in spin trapping experiments designed to show cadmium is not a Fenton active metal. A significant increase of the DMPO/.OH adduct was observed, with increased concentrations of the copper containing MTs, H2O2 enhanced DMPO/.OH adduct formation, catalase and the Cu (I) specific chelating agent bathocuproine, reduced DMPO/.OH adduct formation. These results suggest that Cu (I) and H2O2 both have important roles in the production of active species in these systems and cause DMPO/.OH formation. However, Cd7-MT showed no ability to cause generation of DMPO adducts with H2O2 seeming to indicate cadmium is not a Fenton metal. To test this hypothesis further trapping studies were run with added sulphite and lipid peroxide using both commercial MT and Cd7-MT since cadmium causes peroxidation in vivo. Commercial MT generates radicals with added sulphite and peroxide, Cd7-MT does not, demonstrating that cadmium is not a Fenton metal. These results help to explain the oxidative damage to DNA observed in the presence of MT and cadmium in vitro.


Incidence of endophthalmitis after 20- and 25-gauge vitrectomy causes and prevention.
To compare endophthalmitis incidence after inpatient 20-gauge (20-G) and 25-G vitrectomies, and to examine the causes and prevention of postvitrectomy endophthalmitis. Retrospective, interventional, comparative cohort study. Six thousand nine hundred thirty-five consecutive patients undergoing pars plana vitrectomy. We compared the incidence of endophthalmitis in 3592 consecutive eyes that underwent 20-G vitrectomy between January 2000 and September 2004, and 3343 consecutive eyes that underwent 25-G vitrectomy between April 2004 and December 2007. For 25-G vitrectomy, 542 eyes with sclerotomies produced by straight incision and 2801 eyes with angled incisions were also compared. From 85 eyes that underwent 20-G vitrectomy and 128 eyes that underwent 25-G vitrectomy, ocular surface irrigation fluid and vitreous samples were collected at the end of surgery for bacterial culture. Incidence of postvitrectomy endophthalmitis. The incidence of postoperative endophthalmitis was 0.0278% (1 of 3592 eyes) for 20-G vitrectomies and 0.0299% (1 of 3343 eyes) for 25-G vitrectomies, with no significant difference. Two eyes developed endophthalmitis after vitrectomy, and visual acuity deteriorated to no light perception despite emergency vitreous surgery. The causative bacteria were methicillin-resistant Staphylococcus aureus and Enterococcus faecali; both were resistant to postoperative antibiotics. In 25-G vitrectomy, the endophthalmitis incidence was 0.18% (1/542 eyes) for straight incision versus 0% (0/2801 eyes) for angled incision, with no significant difference (P = 0.1621). Bacterial contamination rates in ocular surface irrigation fluid and the vitreous were 5.9% (5/85 eyes) and 1.2% (1/85 eyes), respectively, in 20-G vitrectomies, and 5.5% (7/128 eyes) and 2.3% (3/128 eyes) in 25-G vitrectomies, with no significant difference. The incidence of endophthalmitis was 0.03% for both 20-G and 25-G vitrectomies. This is the first data set to demonstrate no statistically significant difference between endophthalmitis rates in 20-G and 25-G vitrectomy. At the completion of 25-G vitrectomy, the ocular surface irrigation fluid and vitreous were, on rare occasion, contaminated by antibiotic-resistant bacteria. In 25-G vitrectomy, conjunctival irrigation, ensuring sclerotomy closure, and excision of peripheral vitreous may contribute to the prevention of postvitrectomy endophthalmitis. The authors have no proprietary or commercial interest in any materials discussed in this article.


Mitochondrial calcium efflux and porcine stress-susceptibility.
Mitchondrial Ca2+ efflux rates of M. longissimus dorsi correlate very closely with parameters associated with porcine stress-susceptibility. Experimental data support the measurement of mitochondrial Ca+2 efflux to be a very sensitive and reliable method for differentiating porcine stress-susceptibility.


Metaparadigm: a soft and situation oriented MIS design approach.
Every-day routine work performed by medical staff can be enormous, thus continuing education, diagnostic assistance, medical research or literature searches remains only an aspiration for them. The appearance of the computer-based information technology has initiated the possibility to significantly ease these routine activities and enable the medical staff to devote more time to enhanced creative work. However, only when medical staff can use computers reliably, effectively, democratically, easily, and in natural, intuitive fashion, medical information system (MIS) will be used enthusiastically and favourably. In that manner special attention must be dedicated to MIS design. The aim of our paper is to introduce the new (M)IS design approach called metaparadigm and show its applicability to MIS design. A metaparadigm is a holistic, participative and systemic approach, incorporating design activities needed to construct both the (M)IS design paradigm and the selected (M)IS. It is our deepest belief that metaparadigms employment can enhance many IS design weaknesses and result in the successful medical information systems design and use.


Anomalous self-experiences are related to general cognition deficits in schizophrenia.
Anomalous self-experiences (ASEs) are prevalent in schizophrenia, but its underpinnings are not completely understood. Given the likely complex substrate of the experience of the self, neurocognitive functions requiring coordinate cerebral activity may relate to ASEs. Moreover, cognitive deficits functioning may be involved in the link between self-experience disturbances and some aspects of social dysfunction in schizophrenia. We have assessed ASEs in 41 schizophrenia patients (11 first episodes) using the Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE), and the general cognition using the Brief Assessment of Cognition in Schizophrenia (BACS). Besides, social cognition was assessed using two complementary tools Meyer, Salovey and Caruso Emotional Intelligence Test (MSCEIT) and GEOPTE (Grupo Español para la Optimización del Tratamiento de la Esquizofrenia). The results revealed that Self-awareness/presence and Somatization IPASE scores were inversely explained by motor speed in the BACS; Consciousness IPASE scores were inversely explained by problem solving performance in the BACS. These data reveal a significant relationship between certain domains of general cognition and anomalous self-experiences, that may be useful in further investigation on the substrates of ASEs.


Inhibition of catalase by aminotriazole in vivo results in reduction of glucose-6-phosphate dehydrogenase activity in Saccharomyces cerevisiae cells.
The inhibitor of catalase 3-amino-1,2,4-triazole (AMT) was used to study the physiological role of catalase in the yeast Saccharomyces cerevisiae under starvation. It was shown that AMT at the concentration of 10 mM did not affect the growth of the yeast. In vivo and in vitro the degree of catalase inhibition by AMT was concentration- and time-dependent. Peroxisomal catalase in bakers' yeast was more sensitive to AMT than the cytosolic one. In vivo inhibition of catalase by AMT in S. cerevisiae caused a simultaneous decrease in glucose-6-phosphate dehydrogenase activity and an increase in glutathione reductase activity. At the same time, the level of protein carbonyls, a marker of oxidative modification, was not affected. Possible mechanisms compensating the negative effects caused by AMT inhibition of catalase are discussed.


Multivariable prediction models for the recovery of and claim closure related to post-collision neck pain and associated disorders.
Few clinical prediction models are available to clinicians to predict the recovery of patients with post-collision neck pain and associated disorders. We aimed to develop evidence-based clinical prediction models to predict (1) self-reported recovery and (2) insurance claim closure from neck pain and associated disorders (NAD) caused or aggravated by a traffic collision. The selection of potential predictors was informed by a systematic review of the literature. We used Cox regression to build models in an incident cohort of Saskatchewan adults (n = 4923). The models were internally validated using bootstrapping and replicated in participants from a randomized controlled trial conducted in Ontario (n = 340). We used C-statistics to describe predictive ability. Participants from both cohorts (Saskatchewan and Ontario) were similar at baseline. Our prediction model for self-reported recovery included prior traffic-related neck injury claim, expectation of recovery, age, percentage of body in pain, disability, neck pain intensity and headache intensity (C = 0.643; 95% CI 0.634-0.653). The prediction model for claim closure included prior traffic-related neck injury claim, expectation of recovery, age, percentage of body in pain, disability, neck pain intensity, headache intensity and depressive symptoms (C = 0.637; 95% CI 0.629-0.648). We developed prediction models for the recovery and claim closure of NAD caused or aggravated by a traffic collision. Future research needs to focus on improving the predictive ability of the models.


Uteroplacental blood flow in the hypertensive, term pregnant, spontaneously hypertensive rat.
Carbohydrate overfeeding throughout pregnancy prevents the progressive fall in blood pressure to normotensive levels during the last week of gestation in the spontaneously hypertensive rat. Cardiac output, organ blood flows, and vascular resistances, measured with radioactive-labeled microspheres, were compared in three groups: carbohydrate-supplemented (hypertensive) term-pregnant rats, control-fed (normotensive) term-pregnant rats, and control-fed (hypertensive) nonpregnant rats. Blood pressure remained elevated in the carbohydrate-supplemented pregnant rats because the normal decrease in total peripheral resistance did not occur. There were no significant differences in organ blood flows between hypertensive and normotensive pregnant rats, with the exception of a 26% lower placental blood flow in the hypertensive versus the normotensive rats. Carbohydrate overfeeding was associated with reduced litter size but did not affect fetal growth. Both placental blood flow and litter size were inversely related to mean arterial blood pressure at term. This may be a useful model of essential hypertension during pregnancy.


Value of Thoracic Echocardiography in the Diagnosis of Acute Heart Failure: Systematic Review and Meta-analysis.
For patients with acute heart failure (AHF), the methods of clinical diagnosis of pulmonary edema mainly include clinical symptoms, laboratory results, and an imaging examination. The common diagnostic methods, such as chest X-rays and computerized tomography (CT) scanning, haven't been completely satisfactory. The study intended to systematically, quantitatively, and comprehensively evaluate the value of a lung (pulmonary) ultrasound, performed at a patient's bedside, in the diagnosis of acute heart failure (AHF), to provide an objective basis for its clinical application and further research. The research team searched PubMed, Excerpta Medica Database (EMBASE), ScienceDirect, Cochrane Library, China Journal Full-text Database (CNKI), VIP Full-text Database, Wanfang Database, and China Biomedical Literature Database (CBM) for relevant literature, from January 2010 to the present, about the use of a lung ultrasound for diagnosis of AHF patients. The team used keywords to search literature: ultrasound, AHF diagnosis, cardiogenic pulmonary edema, ultrasonic examination, AHF diagnosis, and cardiogenic pulmonary edema. The research team then conducted a meta-analysis of the collected data according to the Cochrane Handbook 5.3 with RevMan 5.3 statistical software. The study took place at Jinan. The research team: (1) evaluated the quality of the included studies; (2) examined the accuracy of a lung ultrasound in the diagnosis of AHF compared to computerized tomography (CT) as well as to the conventional ultrasonic cardiogram (echocardiogram) that a cardiologist performs; (3) determined the sensitivity, specificity, and predictive value of lung ultrasound using data from two of the included studies; (4) evaluated the data by drawing funnel charts; and (5) examined the publication bias of the included studies. The research team selected six controlled clinical studies, with 345 data samples, for the meta-analysis. The team performed heterogeneity tests for the included research data. For the first test, the team compared the accuracy of lung ultrasound and CT in diagnosing AHF and found obvious heterogeneity, with χ2 = 11.40, df = 3, P = .010, and I2 = 74%. Based on an analysis using a random effects model, the team found no significant differences between the two methods in the diagnosis of AHF (P = .35). For the second test, the team compared the accuracy of lung ultrasound and an ultrasonic cardiogram in diagnosing AHF and found that the data didn't differ significantly, with χ2 = 0.08, df = 1, P = .78, I2 = 0%. Based on an analysis using a fixed effects model, the team found that the accuracy of the lung ultrasound in diagnosing AHF was significantly higher than that of ultrasonic cardiogram (P = .01). In the two studies, the sensitivity and specificity were high. The majority of the funnel charts were symmetrical, but a few were asymmetrical, suggesting a publication bias, which the heterogeneity in the studies and the limited number of examined examples may explain. Lung ultrasound is of great value in the diagnosis of AHF. It's highly efficient, has prospects for broad clinical application, and is worth popularizing, benefiting patients. Scholars need to verify the current study's findings in follow-up studies and in more high-quality case-control trials.


A functional progesterone receptor is required for immunomodulation, reduction of reactive gliosis and survival of oligodendrocyte precursors in the injured spinal cord.
The anti-inflammatory effects of progesterone have been increasingly recognized in several neuropathological models, including spinal cord inflammation. In the present investigation, we explored the regulation of proinflammatory factors and enzymes by progesterone at several time points after spinal cord injury (SCI) in male rats. We also demonstrated the role of the progesterone receptor (PR) in inhibiting inflammation and reactive gliosis, and in enhancing the survival of oligodendrocyte progenitors cells (OPC) in injured PR knockout (PRKO) mice receiving progesterone. First, after SCI in rats, progesterone greatly attenuated the injury-induced hyperexpression of the mRNAs of interleukin 1β (IL1β), IL6, tumor necrosis factor alpha (TNFα), inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), all involved in oligodendrocyte damage. Second, the role of the PR was investigated in PRKO mice after SCI, in which progesterone failed to reduce the high expression of IL1β, IL6, TNFα and IκB-α mRNAs, the latter being considered an index of reduced NF-κB transactivation. These effects occurred in a time framework coincident with a reduction in the astrocyte and microglial responses. In contrast to wild-type mice, progesterone did not increase the density of OPC and did not prevent apoptotic death of these cells in PRKO mice. Our results support a role of PR in: (a) the anti-inflammatory effects of progesterone; (b) the modulation of astrocyte and microglial responses and (c) the prevention of OPC apoptosis, a mechanism that would enhance the commitment of progenitors to the remyelination pathway in the injured spinal cord.


Carbapenem-resistant gram-negative bacterial prevention practice in nosocomial infection and molecular epidemiological characteristics in a pediatric intensive care unit.
The increasing prevalence of carbapenem-resistant gram-negative bacilli infection has emerged as a substantial threat to human health. In January 2017, a screening program for carbapenem-resistant gram-negative bacilli colonization was performed in a pediatric intensive care unit (PICU). Subsequently, different strategies for carbapenem-resistant gram-negative bacilli cohorting and patient placements were introduced in January 2018. The increase in the single room isolation (type A) and the resettlement of the same area placement (type B) resulted in a significant decrease in the nosocomial infection rate from 2.57% (50/1945) in 2017 to 0.87% (15/1720) in 2021 (P < 0.001). Notably, the incidence of nosocomial carbapenem-resistant gram-negative bacilli infections decreased in 2019 (P = 0.046) and 2020 (P = 0.041) compared with that in the respective previous year. During 2019 and 2020, a statistically significant increasing trend of type A and type B placements was observed (P < 0.05, each), which may have contributed to the decline of carbapenem-resistant gram-negative bacilli infection. The primary carbapenemase genes identified in carbapenem-resistant isolates of Klebsiella pneumoniae and Acinetobacter baumannii were blaKPC-2 from sequence type 11 and blaOXA-23 from sequence type 1712. The integration of various placements for patients with carbapenem-resistant gram-negative bacilli infection with active screening has been demonstrated as an effective preventive strategy in the management of carbapenem-resistant gram-negative bacilli infection.


Weighted staffing plans for better prediction of staffing needs.
The aim of this study was to examine the effect of patient turnover and acuity on worked hours per patient day (WHPPD). An examination of staffing plans publically posted by Massachusetts hospitals with more than 300 beds revealed that less than 40% were within 5% of their planned versus actual WHPPD. Three years of WHPPD data collected from 14 adult acute care units were correlated with patient turnover and acuity data. A weight factor was retrospectively added to 8 paired units' planned WHPPD where correlations were identified. Twelve units (86%) showed significant correlations between WHPPD and patient turnover. Correlations between patient acuity and WHPPD were significant only at the aggregate level. After weighting WHPPD, the 8 paired units demonstrated a decreased variance between planned and actual WHPPD. Using a weight factor added to WHPPD to right size acute care medical-surgical units may be useful for accurate staff planning and budgeting.


System for waste disposal reclaims heat.
One hospital's search for a new incinerator that would meet antipollution regulations led to selection and installation of a system that also conserves energy through heat reclamation.


Deep Brain Stimulation in Animal Models of Fear, Anxiety, and Posttraumatic Stress Disorder.
Although medications and psychotherapy are often effective for the treatment of posttraumatic stress disorder (PTSD), 20-30% of patients do not respond to these conventional therapies. In psychiatry, DBS has been either approved or is currently under investigation for different disorders. At present, whether DBS may be used to treat PTSD remains unknown. Preclinical research may provide the scientific rationale for helping conceive and further improve such trials. Some of the animal models commonly used to date are more suitable for investigating mechanisms of anxiety and fear than the long-lasting behavior that characterized PTSD. That said, mechanisms and neurocircuits involved in paradigms such as fear conditioning and extinction share several common features with those of PTSD. In this article, we review preclinical studies in which electrical stimulation has been delivered to animal models of PTSD-like behavior. In those studies, commonly targeted regions were the basolateral amygdala, ventral striatum, hippocampus, and prefrontal cortex. Overall, stimulation delivered at high frequencies to most of these targets improved fear extinction and anxiety-like behavior. Though further research is certainly needed, promising findings from DBS studies in animals are encouraging and suggest a positive future perspective for the field.


Pharmacometric analyses to characterize the effect of CSL112 on apolipoprotein A-I and cholesterol efflux capacity in acute myocardial infarction patients.
To characterize relationships between apolipoprotein A-I (apoA-I) exposure and cholesterol efflux capacity (CEC) and covariate effects following CSL112 (apoA-I [human]) administration in an integrated population including acute myocardial infarction (AMI) patients. A pharmacometric analysis utilized data from seven clinical trials, including patients with AMI, subjects with renal impairment and healthy subjects. A population pharmacokinetic (PK) analysis was performed to relate CSL112 doses to changes in apoA-I plasma concentrations. Covariate analysis was conducted to identify sources of variability in apoA-I exposure. Exposure-response modeling was conducted to describe the relationship between apoA-I exposure and total or ATP binding cassette transporter A1-(ABCA1)-dependent CEC and to identify clinical predictors of CEC. A two-compartment model described apoA-I PK. ApoA-I clearance was slightly lower in subjects with AMI, whereas baseline apoA-I was marginally higher in female and Japanese subjects. Covariate effects on apoA-I exposure were in the order of 10% and thus not clinically relevant. The relationships between apoA-I exposure and CECs were described by nonlinear models. Simulations showed CEC elevation resulting from apoA-I exposure increment was comparable in AMI and non-AMI subjects; no covariate had clinically meaningful effects on CEC. Simulations also demonstrated that CEC in patients with AMI post 6 g CSL112 dosing was substantially elevated compared to placebo and lower dose levels. The model-based exposure-response analysis demonstrated, irrespective of body weight, sex and race, that fixed 6 g CSL112 dosing causes a desired CEC elevation, which may benefit AMI patients by potentially reducing early recurrent cardiovascular event risk.


Chronic comorbid conditions among adult cancer survivors in the United States: Results from the National Health Interview Survey, 2002-2018.
Cancer survivors develop other chronic medical conditions because of shared risk factors and delayed effects of cancer treatment. This study investigated trends in the prevalence of chronic diseases and estimated their population sizes among adult cancer survivors in the United States from 2002 to 2018. Using 2002-2018 National Health Interview Survey data, this study calculated the age-sex-race/ethnicity-adjusted prevalences and estimated the population sizes for the following chronic conditions among cancer survivors: hypertension, diabetes, stroke, heart disease, chronic obstructive pulmonary disease (COPD)/asthma, hepatitis, arthritis, liver disease, kidney disease, and morbid obesity. This study also examined multiple chronic conditions (MCC; 3 or more health conditions). MCC trends were further examined by sociodemographic factors to identify high-risk populations. Parallel analyses were performed for participants without a cancer history to provide a reference. Among 30,728 cancers survivors, increasing trends were observed in the prevalence of hypertension, diabetes, kidney disease, liver disease, and morbid obesity, whereas decreasing prevalence trends were observed for ischemic heart disease, COPD, and hepatitis. Cancer survivors with MCC increased from 4.7 million in 2002 to 8.1 million in 2018 (the prevalence increased from 43.7% to 46.6%). The increase was more pronounced among survivors aged 18 to 44 years. Among adults without a cancer history, the MCC prevalence also increased, although more slowly than among survivors. The number of adult cancer survivors in the United States with comorbid illnesses has increased substantially over the past 2 decades. Optimal management of comorbid conditions and aggressive interventions for risk reduction may benefit the cancer survivor population.


Quantification of the role of tibial posterior slope in knee joint mechanics and ACL force in simulated gait.
The anterior cruciate ligament (ACL) rupture is a common knee joint injury with higher prevalence in female athletes. In search of contributing mechanisms, clinical imaging studies of ACL-injured individuals versus controls have found greater medial-lateral posterior tibial slope (PTS) in injured population irrespective of the sex and in females compared to males, with stronger evidence on the lateral plateau slope. To quantify these effects, we use a lower extremity musculoskeletal model including a detailed finite element (FE) model of the knee joint to compute the role of changes in medial and/or lateral PTS by ±5° and ±10° on knee joint biomechanics, in general, and ACL force, in particular, throughout the stance phase of gait. The model is driven by reported kinematics/kinetics of gait in asymptomatic subjects. Our predictions showed, at all stance periods, a substantial increase in the anterior tibial translation (ATT) and ACL force as PTS increased with reverse trends as PTS decreased. At mid-stance, for example, ACL force increased from 181 N to 317 N and 460 N as PTS increased by 5° and 10°, respectively, while dropped to 102 N and 0 N as PTS changed by -5° and -10°, respectively. These effects are caused primarily by change in PTS at the tibial plateau that carries a larger portion of joint contact force. Steeper PTS is a major risk factor, especially under activities with large compression, in markedly increasing ACL force and its vulnerability to injury. Rehabilitation and ACL injury prevention programs could benefit from these findings.


Acute retinal pigment epitheliitis.
We examined a patient with acute retinal pigment epitheliitis before the development of the characteristic pigmentary retinopathy. Three days after onset of blurred vision in her left eye, a 25-year-old woman had a visual acuity of L.E.: 20/40 -2. There were uniform outer retinal golden-colored vacuoles in the area of subsequent foveal pigmentary alterations. Two months after examination, visual acuity was L.E.: 20/25 -2, and fine subfoveal pigmentary clumping was present. The pigmentary maculopathy of acute retinal pigment epitheliitis may be secondary to primary inflammation of the neurosensory retina.


FBN1 knockout promotes cervical artery dissection by inducing N-glycosylation alternation of extracellular matrix proteins in rat VSMCs.
FBN1 mutation promotes the degeneration of microfibril structures and extracellular matrix (ECM) integrity in the tunica media of the aorta in Marfan syndrome. However, whether FBN1 modulates cervical artery dissection (CAD) development and the potential molecular mechanisms of abnormal FBN1 in CAD remains elusive. In this study, FBN1 deficiency participated in the development of CAD and influenced the proliferation, apoptosis, and migration of vascular smooth muscle cells. FBN1 knockout induced alternations in mRNA levels of the transcriptome, protein expression of the proteome, and abundance of N-glycosylation of the N-glycoproteome. Comprehensive analysis of multiple omics showed up-regulation in mRNA levels of ECM proteins; yet, both the ECM protein levels and relative abundance of N-glycosylation were decreased. Moreover, we performed in vivo experiments to confirm the altered glycosylation of proteins in vascular smooth muscle cells. In conclusion, FBN1 deletion in vascular smooth muscle cells can result in altered N-glycosylation of ECM protein, which were critical for the stability of ECM and the process of CAD. This may open the way for a novel therapeutic strategy to treat people with CAD.


Road traffic crash characteristics of drivers who take prescription medicines that carry a risk to driving.
The specific features of crashes involving an alcohol-intoxicated driver have been extensively characterized, but no such data are available for crashes involving a driver who has used a prescription medicine, which could help to plan and target prevention and control initiatives. This study aimed to describe the characteristics of crashes involving drivers under the influence of prescription medicines. We took advantage of CESIR, a French record linkage study for which data were extracted and matched from three French national databases: police reports, the national police database of injurious crashes and the national health care insurance database (HCI database). The drivers included in the study were those involved in an injurious road crash in France from July 1, 2005 to December 31, 2015, whose national identity number, date of birth and sex allowed matching. Prescription medicines considered were those with the two highest levels of warning. Similar crash profiles were found when drivers used alcohol or medicines, particularly with respect to injury severity, type of vehicle, type of collision, type of road and cross-track profile. Alcohol-related crashes were over-represented during weekends and in low-density areas and medicine-related crashes were over-represented during weekdays and in cities of fewer than 300 000 inhabitants. While a much higher strength of association with responsibility was found for alcohol than for medicines, the proportion of crashes with drivers using medicines was twice as high as crashes with drivers using alcohol. The lower risk carried by medicines is therefore in part compensated by a higher prevalence of use, making medicines one of the hidden factors of road risk. Characterizing these crashes will therefore be useful to better focus road safety intervention on the prevention of driving under the influence of psychotropic medicines.


[Zollinger-Ellison syndrome with high blood calcium levels resembling the neoplastic type (author's transl)].
A patient with the Zollinger-Ellison syndrome was found to have increased blood gastrin levels associated with the secretion of a compound which produced high blood calcium levels. This compound differed from immunoreactive parathormone, and caused the clinical picture of primary neoplastic hyperparathyroidism. This case is compared with other cases of multiple-secreting Zollinger-Ellison syndrome reported in the published literature, within the framework of the "A.P.U.D." system.


Ferulic acid, a natural polyphenol, alleviates insulin resistance and hypertension in fructose fed rats: Effect on endothelial-dependent relaxation.
Ferulic acid (FER) is a polyphenolic compound contained in various types of fruits. It has a substantial therapeutic effect inhibitory activity against aldose reductase (AR) inhibition. In this study, we examined the effect of FER on fructose-fed rats in comparison to a standard AR inhibitor, zopolrestat (ZOP). We determined the protective role of FER against metabolic syndrome by examining serum insulin/Glucose levels, triglycerides (TGs), cholesterol and advanced glycation end product (AGE) in rats supplied with 10% fructose drinking water. In addition, blood pressure, vascular reactivity of isolated thoracic aortas and acetylcholine-induced NO were all evaluated to estimate the cardiovascular complications of metabolic syndrome (MetS) associated with fructose feeding. Animals were randomly divided into four groups: control, (+10% fructose, Fru), zopolrestat-treated fructose fed (Fru-zop) and ferulic acid-treated fructose fed rats (Fru-Fer). After 12 weeks of FER treatment, we found significant reduction in both hyperinsulinemia and elevated diastolic blood pressure associated with fructose-fed to levels comparable to those achieved with ZOP. Both FER and ZOP significantly augmented the impaired relaxation associated with fructose-fed, whereas neither showed any significant effect on the developed vasoconstriction. Isolated aortas from fructose-fed rats incubated with either FER or ZOP, reinstated normal relaxation response to acetylcholine (ACh). Furthermore, isolated aortas showed attenuated nitric oxide (NO) production following the addition of (ACh), while both FER and ZOP restored normal induction of NO. Taken together, the current study shows that, FER alleviated insulin resistance and hypertension associated with metabolic syndrome compared to the standard AR inhibitor (ZOP). This potential protective effect is at least mediated by restoring endothelial relaxation.


A novel proteomic approach identifies new interaction partners for proliferating cell nuclear antigen.
During DNA replication and repair, many proteins bind to and dissociate in a highly specific and ordered manner from proliferating cell nuclear antigen (PCNA). We describe a combined approach of in silico searches at the genome level and combinatorial peptide synthesis to investigate the binding properties of hundreds of short PCNA-interacting peptides (PIP-peptides) to archaeal and eukaryal PCNAs. Biological relevance of our combined approach was demonstrated by identification an inactive complex of Pyrococcus abyssi ribonuclease HII with PCNA. Furthermore we show that PIP-peptides interact with PCNA largely in a sequence independent manner. Our experimental approach also identified many so far unidentified PCNA interacting peptides in a number of human proteins.


Efficacy and safety of Gyejibokryeong-hwan (GBH) in major depressive disorder: study protocol for multicentre randomised controlled trial.
Gyejibokryeong-hwan (GBH) is an herbal medicine composed of five herbs. It has been widely used to treat gynaecological diseases in traditional East Asian medicine. Recent animal studies suggest antidepressant effects of GBH. In this trial, we explore the efficacy and safety of GBH in patients with major depressive disorder and to identify the optimal dose for the next phase III trial. This trial will enrol 126 patients diagnosed with major depressive disorder and not treated with antidepressants. Participants will be randomised to receive a high or a low dose of GBH or placebo granules. The study drugs will be administered three times a day, for 8 weeks. The 17-item Hamilton Depression Rating Scale (HDRS) will be used to measure the severity of depressive symptoms at weeks 2, 4, 6, 8, and 12. The primary efficacy endpoint is the change from baseline in HDRS-17 total score post-treatment at week 8. Analysis of covariance will be based on the baseline HDRS-17 total score and site as the covariates. Safety assessment will be based on the frequency of adverse events. The severity and causality of the study drug will be assessed. This study is designed to evaluate the efficacy and safety of GBH granules compared with placebo in patients with major depressive disorder. Clinical Research Information Service KCT0004417 . Registered on November 1, 2019 (prospective registration).


Three-dimensional reconstruction of a membrane-bending complex: the RC-LH1-PufX core dimer of Rhodobacter sphaeroides.
A three-dimensional model of the dimeric reaction center-light harvesting I-PufX (RC-LH1-PufX) complex from Rhodobacter sphaeroides, calculated from electron microscope single particle analysis of negatively stained complexes, shows that the two halves of the dimer molecule incline toward each other on the periplasmic side, creating a remarkable V-shaped structure. The distribution of negative stain is consistent with loose packing of the LH1 ring near the 14th LH1 alpha/beta pair, which could facilitate the migration of quinone and quinol molecules across the LH1 boundary. The three-dimensional model encloses a space near the reaction center Q(B) site and the 14th LH1 alpha/beta pair, which is approximately 20 angstroms in diameter, sufficient to sequester a quinone pool. Helical arrays of dimers were used to construct a three-dimensional membrane model, which matches the packing lattice deduced from electron microscope analysis of the tubular dimer-only membranes found in mutants of Rba. sphaeroides lacking the LH2 complex. The intrinsic curvature of the dimer explains the shape and approximately 70-nm diameter of these membrane tubules, and at least partially accounts for the spherical membrane invaginations found in wild-type Rba. sphaeroides. A model of dimer aggregation and membrane curvature in these spherical membrane invaginations is presented.


The effect of hematocrit and systolic blood pressure on cerebral blood flow in newborn infants.
The effects of hematocrit and systolic blood pressure on cerebral blood flow were measured in 15 stable, low birth weight babies. CBF was measured with a modification of the xenon-133 (133Xe) clearance technique, which uses an intravenous bolus of 133Xe, an external chest detector to estimate arterial 133Xe concentration, eight external cranial detectors to measure cephalic 133Xe clearance curves, and a two-compartmental analysis of the cephalic 133Xe clearance curves to estimate CBF. There was a significant inverse correlation between hematocrit and CBF, presumably due to alterations in arterial oxygen content and blood viscosity. Newborn CBF varied independently of systolic blood pressure between 60 and 84 mm Hg, suggesting an intact cerebrovascular autoregulatory mechanism. These results indicate that at least two of the factors that affect newborn animal CBF are operational in human newborns and may have important clinical implications.


Effect of prostaglandins and hormones on cyclic AMP formation in rat hepatomas and liver tissue.
The formation of cyclic AMP was studied in normal liver, subcutaneous hepatomas derived from MH1C1 cells, and premalignant liver and primary hepatomas induced by the carcinogens 2-acetylaminofluorene (AAF) and 4-dimethylamino-azobenzene (DAB). While only very slight effects of prostaglandins (PG) were seen in slices of normal liver, all the hepatomas responded strongly to PGE1 and PGE2. The hepatomas also had increase PGE1-sensitive adenylate-cyclase activity. PGF1alpha and PGF2alpha did not increase the cAMP level significantly either in the liver or in the hepatomas. During AAF carcinogenesis the response to PGE1 increased slightly during the carcinogen feeding, and was greatly elevated only in the fully developed hepatomas. This is in contrast to the increase in adrenalin response seen during carcinogenesis, which starts much earlier, and reaches a peak value within 8--10 weeks. It is concluded that various hepatomas have elevated responsiveness to PGE1 and PGE2 as well as to adrenalin, but the course of change in the tissues' ability to respond to these agents during carcinogenesis is very different.


[The Woman and the Care of Life. Historical Understanding and Future Perspectives].
Over the ages of humanity, women has established a special relationship life care's with the most vulnerable. Women dedicated to the professional care have always existed, also to the unpaid home care of the sick, elderly, with some disability, and children. This study has been carried out a historical and current verification of this question, marking its most characteristic and significant features. From that perspective, we tried to answer these key questions: causes that have motivated this fact, its social consequences and, finally, the most important future implications for all, men and women that, surely, we will be caregivers and strapped for care in our illness.


Quantitative determination of expression of the prostate cancer protein alpha-methylacyl-CoA racemase using automated quantitative analysis (AQUA): a novel paradigm for automated and continuous biomarker measurements.
Despite years of discovery and attempts at validation, few molecular biomarkers achieve acceptance in the clinical setting. Tissue-based markers evaluated by immunohistochemistry suffer from a high degree of inter- and intraobserver variability. One recent advance in this field that promises to automate this process is the development of AQUA, a molecular-based method of quantitative assessment of protein expression. This system integrates a set of algorithms that allows for the rapid, automated, continuous, and quantitative analysis of tissue samples, including the separation of tumor from stromal elements and the subcellular localization of signals. This study uses the AQUA system to assess a recently described prostate cancer biomarker, alpha-methylacyl-CoA-racemase (AMACR), and to determine the effectiveness of the quantitative measurement of this marker as a means for making the diagnosis of prostate cancer. Using a prostate cancer progression tissue microarray containing a wide range of prostate tissues, AQUA was directly compared to standard immunohistochemical evaluation for AMACR protein expression using the p504s monoclonal antibody. Both methods produced similar results showing AMACR protein expression to be strongest in the clinically localized prostate cancer, followed by the metastatic tumor samples. Benign prostate tissue was categorized as negative for most tissue samples by immunohistochemistry. However, AMACR was detectable using the AQUA system at low levels using the standard 1:25 dilution but also at 1:250 dilution, which is not detectable by light microscopy. The AQUA system was also able to discriminate foamy gland prostate cancers, which are known to have a lower AMACR expression than typical acinar prostate cancers, from benign prostate tissue samples. Finally, a receiver-operating-characteristic curve was plotted to determine the specificity of the AMACR AQUA Z-score (normalized AQUA score) to predict that a given tissue microarray sample contains cancer. The area under the curve was calculated at 0.90 (P < 0.00001; 95% CI, 0.84 to 0.95). At an AMACR AQUA Z-score score of -0.3, 91% of the 70 samples classified as prostate cancer were correctly categorized without the intervention of a pathologist reviewing the tissue microarray slide. In conclusion, the AQUA system provides a continuous measurement of AMACR on a wide range of prostate tissue samples. In the future, the AMACR AQUA Z-score may be useful in the automated screening and evaluation of prostate tissue biomarkers.


Camptothecine production by mixed fermentation of two endophytic fungi from Nothapodytes nimmoniana.
Two endophytic fungi isolated from the endangered plant Nothapodytes nimmoniana (Grah.) Mabb. were found to effectively synthesize CPT independent of their host plant under submerged fermentation conditions. Molecular characterization of fungi revealed their identity as Colletotrichum fructicola SUK1 (F1) and Corynespora cassiicola SUK2 (F2). Mixed fermentation experiments were carried out to study the effect of microbial signalling between the two fungal species on camptothecine production. Effect of culture parameters on CPT production was studied for both mono-cultures (F1 and F2) separately as well as for the mixed fermentation (F1 + F2). Further the most influencing ones were optimized statistically using response surface methodology. Statistical model based optimized parameters were whey (70 %), agitation rate (110 rpm), temperature (30 °C), and incubation period (7 d) for the mixed fermentation. Monocultures of the two fungal species F1 and F2 yielded CPT up to 33 ± 1.1 mg l(-1)and 69 ± 1.1 mg l(-1), respectively; while their mixed fermentation under the optimized conditions yielded up to 146 ± 0.2 mg l(-1). HPLC and LC-MS/MS techniques were used to analyze the products obtained.


A rare case of direct tumor extension to the right ventricle.
We report the case of a 72-year-old woman with signs of pulmonary embolism and right heart failure. Echocardiographic imaging and computed tomography revealed a mass within the inferior vena cava reaching from the head of the pancreas to the right ventricle. From standard imaging procedures and clinical findings alone, differentiation of a cardiac thrombus from a metastatic tumor mass was difficult. After resection of the intravascular tumor, histopathologic analysis confirmed a metastasis of primary ductal pancreatic adenocarcinoma. This is a report of a case of mucinous adenocarcinoma of the pancreas reaching the heart by continuous intravascular spreading.


Applicability of the functional gene catechol 1,2-dioxygenase as a biomarker in the detection of BTEX-degrading Rhodococcus species.
Catechol 1,2-dioxygenase is a key enzyme in the degradation of monoaromatic pollutants. The detection of this gene is in focus today but recently designed degenerate primers are not always suitable. Rhodococcus species are important members of the bacterial community involved in the degradation of aromatic contaminants and their specific detection could help assess functions and activities in the contaminated environments. To reach this aim, specific PCR primer sets were designed for the detection of Rhodococcus related catechol 1,2-dioxygenase genes. Primers were tested with genetically well-characterized strains isolated in this study and community DNA samples were used as template for Rhodococcus specific PCR as well. The sequences of the catabolic gene in question were subjected to multiple alignment and a phylogenetic tree was created and compared to a 16S rRNA gene based Rhodococcus tree. A strong coherence was observed between the phylogenetic trees. The results strongly support the opinion that there was no recent lateral gene transfer among Rhodococcus species in the case of catechol 1,2-dioxygenase. In gasoline contaminated environments, aromatic hydrocarbon degrading Rhodococcus populations can be identified based upon the detection and sequence analysis of catechol 1,2-dioxygenase gene.


Cholesterol-depleting compounds modulate K+-currents in Drosophila Kenyon cells.
Sterol-enriched lipid rafts have been involved in Drosophila membrane signalling such as Hedgehog targeting and glutamate receptor ligand-affinity regulation. Here, we show that the voltage-dependent K(+) currents expressed by the intrinsic neurons of the Mushroom bodies are upward-modulated by compounds that remove sterols from the plasma membrane. Modulation seems to rely on a fast-exchanging sterol-pool, which more strongly affects the slowly inactivating current. Our results provide the first evidence that sterols influence the operation of voltage-gated ion channels in Drosophila neurons and strengthen the importance of lipid rafts in this biological model.


Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit.
The major events of the cell division cycle are triggered by periodic changes in the activity of cyclin-dependent protein kinases (CDKs). In mammals, the members of the CDK family include CDK2 and CDC2, which are thought to be involved in the control of DNA replication and mitosis, respectively. The protein kinase activity of these enzymes is controlled by a complex array of mechanisms. Activation of the CDK catalytic subunit requires association with a positive regulatory subunit (cyclin) and phosphorylation (at Thr 160 in CDK2). This activated complex can be inhibited by additional phosphorylation at Thr 14 and Tyr 15. Here we report the identification of a new mechanism for the regulation of CDK2 activity. We find that CDK2/cyclin complexes in mouse fibroblasts associate tightly with a 20K protein (CAP20). Complexes containing CAP20 were isolated from cell lysates and found to have negligible kinase activity, indicating that CAP20 association in vivo may inhibit CDK2 activity. We purified CAP20 from 3T3 cells and found that low concentrations of the protein completely inhibit the kinase activity of CDK2 in vitro. Thus CAP20 represents a new negative regulatory subunit that inhibits the activity of CDK2/cyclin complexes in mammalian cells.


Randomized Study of a New Noninvasive Skin Closure Device for Use After Congenital Heart Operations.
We report a new, noninvasive Zip surgical skin closure device (ZipLine Medical, Campbell, CA). This device is considered to have good cosmetic outcomes after operations and reduces surgical time. In this study, skin closure using the Zip device was compared with subcuticular sutures and the usefulness and safety of this new device was evaluated. This was a prospective, randomized study of 214 patients who underwent cardiac operations through a median sternotomy from June 2014 to December 2015. In 136 patients, this was a first operation group of which 71 patients underwent Zip surgical skin closure (Zip group), and 65 patients underwent subcuticular sutures (suture group). In 78 patients, this was a reoperation group, of which 42 patients were in the Zip group and 36 patients were in the suture group. Cosmetic results using the Vancouver Scar Scale were evaluated separately in the first operation group and reoperation group. There were significant differences in the total Vancouver Scar Scale score between the first operation group (p < 0.001) and reoperation group (p = 0.007). The skin closure time was significantly shorter in the Zip group than in the suture group (113.0 ± 9.1 seconds vs 375.9 ± 60.2 seconds, p < 0.001). No significant differences were found regarding the rate of surgical site infection between the groups. Complications peculiar to this device included skin discoloration (0.9%), epidermolysis (0.9%), and exfoliation of the device (1.8%); however, no serious complications developed. In congenital heart operations through a median sternotomy, the Zip surgical skin closure device was an excellent choice for improving the cosmetic appearance and reducing the wound closure time. In addition, it proved to be a device that could be used safely.


When holistic care is not holistic enough: The role of sexual health in mental health settings.
To explore the preparation that mental health nurses receive to address sexual health in practice. People who use the mental health services often have complex sexual health needs. Mental health nurses are well placed to offer support. However, this rarely happens in practice, and therefore, people's sexual health needs are not being routinely addressed. It is not known why this is the case. Systematic review and meta-ethnography. EBSCO, PsycINFO, MEDLINE and ASSIA databases were searched using Booleans with Mesh and key terms including "mental health nurse" and "sexual health". Date range was June 2006 to June 2016. Discursive papers were excluded. Included papers (n = 7) were synthesised using a meta-ethnographic approach. The search yielded seven studies. Five key themes were identified: the (not so) therapeutic relationship; personal values dictating professional ones; institutionalised fear; being human; and education: the answer but where is it? The findings illustrate the complexity of supporting people with mental health and sexual health needs. They show the discomfort many nurses have about broaching sexual health. Arguably more than with most issues, personal values impacted strongly on professional practice. Understanding the depth and multifaceted nature of these themes is important, because strategies can then be developed to mitigate the barriers to best practice. For example, the findings presented here offer a framework from which structured education and support can be built. There is a need for Mental health nurses to be more responsive to concerns around sexual health and it should be routinely included in their practice. This study illuminates why this is not currently the case. By understanding this, remedial action can be taken by nurse educators. Implications are also discussed in relation to policy, research and practice.


CDMOs Play a Critical Role in the Biopharmaceutical Ecosystem.
Biopharmaceutical industries have advanced significantly after the millennium. Novel biopharmaceuticals have been developed one after another, and blockbuster drugs have been produced. Accompanying the increase in the demand for biopharmaceuticals, a business model called "contract development manufacturing organization (CDMO)" has emerged. A CDMO is entrusted with the development and manufacturing of production processes from pharmaceutical companies. In this review, we identify the success factors of the biopharmaceutical CDMO by analyzing the foundry business for the semiconductor industry. Furthermore, we also review monoclonal antibody production platforms and new technologies that are critical aspects of differentiation strategies in the biopharmaceutical CDMO.


Discovery of a Novel Inhibitor of the Protein Tyrosine Phosphatase Shp2.
Shp2 is a ubiquitously expressed protein tyrosine phosphatase (PTP) related to adult acute myelogenous leukemia and human solid tumors. In this report, we describe identification of a potent Shp2 inhibitor, Fumosorinone (Fumos) from entomogenous fungi, which shows selective inhibition of Shp2 over other tested PTPs. Using a surface plasmon resonance analysis, we further confirmed the physical interaction between Shp2 and Fumos. Fumos inhibits Shp2-dependent activation of the Ras/ERK signal pathway downstream of EGFR, and interrupts EGF-induced Gab1-Shp2 association. As expected, Fumos shows little effects on the Shp2-independent ERK1/2 activation induced by PMA or oncogenic Ras. Furthermore, Fumos down-regulates Src activation, inhibits phosphorylation of Paxillin and prevents tumor cell invasion. These results suggest that Fumos can inhibit Shp2-dependent cell signaling in human cells and has a potential for treatment of Shp2-associated diseases.


Methods of midtrimester abortion: which is safest?
In the United States, the three principal methods of abortion for patients at 13 or more menstrual weeks' gestation are intraamniotic instillation of saline or prostaglandin F2alpha (PGF2alpha) and dilatation and evacuation (D&E). The relative safety of these methods, however, has not been established. This report compares the three methods using data on 17467 abortions collected by the Joint Program for the Study of Abortion under the auspices of the Center for Disease Control (JPSA/CDC). Abortion by D&E was found to be significantly safer than abortion by saline instillatin (p less than 0.001), and abortion by saline instillation was significantly safer than by PGF2alpha (p less than 0.01). Moreover, midtrimester D&E is both safe and practical; it is a direct and rapid procedure which can be performed on an outpatient basis. Although PGF2alpha accelerated the time required for abortion, it also significantly increased serious morbidity.


Multiparametric analysis for the determination of radon potential areas in buildings on different soils of volcanic origin.
The transposition of the European EURATOM directive into the regulations of the different member states of the European Union involved governments making great efforts to define priority action maps against indoor radon exposure in buildings over a short time period. In Spain, the Technical Building Code established 300 Bq/m3 as a reference level and set up a classification of municipalities in which remediation measures should be adopted for radon exposure in buildings. Oceanic volcanic islands, such as the Canary Islands, present high geological heterogeneity in a small space due to their volcanic origin. This variability poses a challenge to the elaboration of radiological risk maps, which makes it necessary to have a high density of data to collect local variations. This paper presents a methodology to obtain accurate radon risk maps based on geological criteria and terrestrial gamma radiation. The predictive efficiency of these maps is statistically verified using indoor radon concentration data measured in buildings. Other radiological variables, which are commonly used as criteria for radon risk prediction found in the literature, were also applied, such as the geogenic radon potential and the activity concentration of natural radioisotopes in soils. The higher resolution of the maps obtained allows for a more detailed classification of radon risk zones in the study area than the current risk maps published in the Spanish building regulations.


Immunotherapy of hematologic malignancies and metastatic solid tumors in experimental animals and man.
Following engraftment of donor hematopoietic cells and induction of host-versus-graft tolerance, immunocompetent lymphocytes of donor origin can induce graft-versus-leukemia (GVL) and graft-versus-tumor (GVT) effects. Engraftment of allogeneic bone marrow cells can be accomplished following non-myeloablative conditioning while possibly controlling graft-versus-host disease (GVHD). GVL and GVT effects may thus be successfully accomplished following non-myeloablative stem cell transplantation (NST) as shown by data derived from experimental animals and man.


Measured effects of various electrolyte and capillary properties in dielectric barrier electrospray ionization: development of a comprehensive model.
The mechanism which leads to a dielectric barrier electrospray (DB-ES) was investigated by measurements of the electrical current. It comprises several components, namely, the displacement current, currents which are initiated by electromagnetic transmission, an ion current inside the capillary, which is responsible for the built-up of the potential at the tip, and the electrospray current as a result of the displacement current and the ion transfer current. An augmented interpretation of the current signal of the DB-ES is presented, and features are described in more detail. The behavior of the ions inside the capillary and the charge transfer are described from the chemical and the electrical point of view.


Conformation changes of albumin and lysozyme on electrospun TiO2 nanofibers and its effects on MSC behaviors.
Protein adsorption plays a key role in bone repair and regeneration by affecting cell behavior. In this study, TiO2 nanofibers (TiO2 NFs) with different structures, including anatase TiO2 nanofibers (A-NFs), anatase TiO2 nanofibers with beads (B-NFs), anatase-rutile TiO2 nanofibers (AR-NFs) and rutile TiO2 nanofibers (R-NFs), were prepared by electrospinning method. Bovine serum albumin (BSA) and lysozyme (LYZ) were used to explore the adsorption behaviors of TiO2 NFs and then the effects of materials with protein on bone marrow mesenchymal stem cells (MSCs) were studied. Pure titanium metal (PT) was used as control. The results displayed that the adsorption amounts of BSA on samples were B-NFs > AR-NFs > A-NFs ≈ R-NFs > PT, and that for LYZ were B-NFs > AR-NFs > R-NFs > A-NFs > PT. The conformation of proteins changed remarkably when they were adsorbed on meterials. Soaking the TiO2 NFs with and without protein into SBF revealed that the BSA and LYZ on B-NFs, A-NFs and AR-NFs could accelerate the HA deposition on its surface, but it had no promoting effect on HA deposition on B-NFs. MTT and PCR tests showed that the BSA and LYZ adsorbed on materials could promote the proliferation and osteogenic differentiation of MSCs to different degrees due to their different adsorption amount and conformation changes on different TiO2 NFs. The current work demonstrated that the surface properties and crystal structure of TiO2 NFs could influence the adsorption behavior and conformational change of BSA and LYZ, and then further regulate MSCs biological behavior.


Effect of salinity on methanogenic propionate degradation by acclimated marine sediment-derived culture.
Degradation of propionate under high salinity is needed for biomethane production from salt-containing feedstocks. In this study, marine sediment-derived culture was evaluated to determine the effect of salinity on methanogenic propionate degradation. Microbes in marine sediments were subjected to fed-batch cultivation on propionate for developing acclimatized cultures. The rate of propionate degradation increased eightfold during 10 rounds of cultivation. Microbial community composition was determined through pyrosequencing of 16S rRNA gene amplicons after 10 rounds of cultivation. Taxa analysis was conducted for the reads obtained by pyrosequencing. Known propionate degraders were undetectable in the acclimated culture. Comparison of bacterial taxa in the original sediment with those in the acclimated culture revealed that the populations of four bacterial taxa were significantly increased during acclimation. Methanolobus was the predominant archaea genus in the acclimated culture. The propionate degradation rate of the acclimated culture was not affected by salinity of up to equivalent of 1.9 % NaCl. The rate decreased at higher salinity levels and was more than 50 % of the maximum rate even at equivalent of 4.3 % NaCl.


Arterial Perfusion of the Proximal Phalanx Revisited: New Insights Based on Micro-Computed Tomography.
To characterize the periosteal and endosteal arterial perfusion of the proximal phalanx using micro-computed tomography angiography (micro-CTA). Cadaveric upper extremities were injected with a barium sulfate/gelatin suspension. Phalanges were imaged using micro-CTA and analyzed with a focus on osseous arterial anatomy. Periosteal and endosteal perfusion was characterized by number of vessels, length, anatomic course, and caliber. The base of the proximal phalanx had a significantly greater number (8.0 ± 3.5) of periosteal vessels than those of the shaft (4.1 ± 1.6) and head (1.3 ± 1.1). One-third (34.4%) of the specimens demonstrated a complete absence of periosteal vessels in the head. A nutrient endosteal vessel was noted in 100% of the specimens. Entering at the junction of the middle and distal third of the bone (25.8 ± 3.9 mm from base), the nutrient vessel entered the proximal phalanx of the index finger along its ulnar aspect (8 of 8 specimens), the middle finger along its radial aspect (6 of 8), the ring finger along its ulnar aspect (5 of 8), and the little finger along its radial aspect (7 of 8). The nutrient vessel branched into proximal and distal extensions toward the shaft and head, respectively, with an average endosteal length of 10.7 ± 5.2 mm and average diameter of 0.36 ± 0.11 mm. Periosteal contributions to the perfusion of the proximal phalanx appear to diminish distally. The endosteal arterial anatomy remains consistent, with a single nutrient vessel entering the intramedullary canal with reliable laterality on each digit. This is often the only vessel supplying the head of the proximal phalanx, making this area particularly susceptible to vascular compromise. An understanding of the patterns of perfusion of the proximal phalanx provides some insight into clinically observed pathology, as well as guidance for operative management.


Voltammetric determination of the herbicide Linuron using a tricresyl phosphate-based carbon paste electrode.
This paper summarises the results of voltammetric studies on the herbicide 3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea (Linuron), using a carbon paste electrode containing tricresyl phosphate (TCP-CPE) as liquid binder. The principal experimental conditions, such as the pH effect, investigated in Britton-Robinson buffer solutions (pH 2.0-7.0), the peak characteristics for the analyte of interest, or instrumental parameters for the differential pulse voltammetric mode were optimized for the method. As found out, the best electroanalytical performance of the TCP-CPE was achieved at pH 2.0, whereby the oxidation peak of Linuron appeared at ca. +1.3 V vs. SCE. The analytical procedure developed offers good linearity in the concentration range of 1.25-44.20 μg mL(-1) (1.77 × 10(-4)-5.05 × 10(-6) mol L(-1)), showing-for the first time-the applicability of the TCP-CPE for anodic oxidations in direct voltammetry (without accumulation). The method was then verified by determining Linuron in a spiked river water sample and a commercial formulation and the results obtained agreed well with those obtained by the reference HPLC/UV determination.


Cost-Effectiveness and Cost-Utility Analyses in Thailand of Continuous Intrathecal Morphine Infusion Compared with Conventional Therapy in Cancer Pain: A 10-year Multicenter Retrospective Study.
Because of the high initial cost of intrathecal drug delivery (ITDD) therapy, this study investigated the cost-effectiveness and cost-utility of ITDD therapy in refractory cancer pain management in Thailand over the past 10 years. The retrospective study was conducted in patients with cancer pain who underwent ITDD therapy from January 2011 to 2021 at three university hospitals. Clinical outcomes included the numerical rating scale (NRS), Palliative Performance Scale, and the EQ-5D. The direct medical and nonmedical as well as indirect costs were also recorded. Cost-effectiveness and cost-utility analyses were performed comparing ITDD therapy with conventional therapy (extrapolated from costs of the same patient before ITDD therapy) from a societally oriented economic evaluation. Twenty patients (F:M: 10:10) aged 60 ± 15 years who underwent implantation of an intrathecal percutaneous port (IT port; n = 15) or programmable intrathecal pump (IT pump; n = 5) were included. The median survival time was 78 (interquartile range = 121-54) days after ITDD therapy. At 2-month follow-up, the incremental cost-effectiveness ratio (ICER)/pain reduction of an IT port (US$2065.36 (CA$2829.54)/2-point NRS reduction/lifetime) was lower than for patients with an IT pump (US$5479.26 (CA$7506.58)/2-point NRS reduction/lifetime) compared with continued conventional therapy. The ICER/quality-adjusted life years (QALYs) gained for an IT port compared with conventional treatment was US$93,999.31(CA$128,799.06)/QALY gained, which is above the cost-effectiveness threshold for Thailand. The cost-effectiveness and cost-utility of IT port therapy for cancer pain was high relative to the cost of living in Thailand, above the cost-effectiveness threshold. Prospective cost analysis studies enrolling more patients with diverse cancers that investigate the benefit of early ITDD therapy with devices over a range of prices are warranted.


Long-term results of the two-stage palatoplasty/Hotz' plate approach for complete bilateral cleft lip, alveolus and palate patients.
To investigate the effects of the two-stage palatoplasty combined with the Hotz' plate on craniofacial development in patients with bilateral complete clefts. Lateral and frontal cephalograms of two-stage palatoplasty/Hotz' plate group (n=10), one-stage palatoplasty group (n=11), and a non-cleft group (n=11), were evaluated at 6, 8, 10 and 12 years of age. The unpaired Student's t-test and Scheffe's F test (p<0.05) were applied. At 6 years the posterior upper facial height (PUFH) and PUFH/PFH ratio were greater in the two-stage group. At 10 years the PUFH, maxillary depth, convexity and ANB angle were greater in the same group. At 12 years, maxillary depth and ANB angle were also greater in this group. In the one-stage group, the L1/Mp. angle, PUFH and PUFH/PFH ratio were smaller when compared with the non-cleft group, whereas the palatal plane/SN angle was greater. In both cleft groups, the I.I. angle and tongue-PTM' distance were greater, and the U1/SN angle was smaller when compared with non-clefts. The UC-UC' and the ratios UC/MAX and UC/LC of both cleft groups were also smaller when compared with non-clefts. The ratio UM/MAX of the one-stage group was smaller when compared with the non-cleft group. The two-stage palatoplasty in combination with application of the Hotz' plate had good effects on the maxillary growth up to the age of 12 years.


Variations of the iliac and pelvic venous systems with special attention to the drainage patterns of the ascending lumbar and iliolumbar veins.
The anatomy of the inferior vena cava (IVC) and common, external and internal iliac veins (CIV, EIV, IIV respectively) was examined in 59 embalmed adult human cadavers of Caucasian origin. In the present study, we focus our attention on the drainage patterns of the ascending lumbar and iliolumbar veins (ALV, ILV) when there are variations in the major pelvic veins by highlighting and describing the variations themselves. The above patterns, when no variations exist, have already been reported. Among the 59 cadavers, nine (9/59, 15.3%) presented anomalies of the major pelvic veins, as follows: anomalous drainage of both EIV and IIV in 8.5% of the specimens (5/59, Type I); variations of the IVC in 3.4% (2/59, Type II); duplication of the IIV (1/59=1.7%, Type III); anastomotic branch between the right IIV and the left CIV (1/59=1.7%, Type IV). ALV drained either into the CIV (8/18 sides, 44.4%) or in EIV (5/18 sides, 27.8%), while absence of ILV was the most frequent pattern (8/18 sides, 44.4%). A common trunk, joining the two veins, was observed in 5/18 sides (27.8%). Those drainage patterns were in accordance with the ones discovered in our previous study. In Type I the two veins always drained into the EIV. Knowledge of the surgical anatomy of all studied veins may prevent injury to these veins during operations in the retroperitoneal space and pelvis or malposition of venous catheters placed from the groin.


Carrying food items to cover for consumption: the behavior of ten bird species feeding under the risk of predation.
In earlier work (Lima et al. 1985; Lima 1985), we found that gray squirrels (Sciurus carolinensis) and black-capped chickadees (Parus atricapillus) when exploiting a patch of food in the open often carried individual food items to protective cover for consumption. Their tendency to carry (i) decreased as distance of the patch from cover increased, and (ii) increased as size of the available food items increased. A simple model indicated that this behavior was consistent with a trade-off between efficient foraging and predation risk. Maximal feeding efficiency was achieved by always eating at the patch, whereas minimal time exposure to predators was achieved by carrying all items to cover for consumption. Because predation-riskrelated trade-offs are likely to be of importance in the determination of feeding behavior, we surveyed the behavior of 10 bird species feeding under similar conditions to assess both the generality of the above results and the adequacy of some simple assumptions concerning the assessment and perception of predation risk.We observed considerable interspecific variability in behavior. Of the 10 species studied, 4 behaved in a manner similar to the squirrels and chickadees. Five other species showed an increased tendency to carry with larger items but no clear tendency to decrease carrying from longer distances. The one remaining species exhibited neither behavioral trend.The model that predicted squirrel and chickadee behavior failed to account for all observed behavior. The behavior of all species, however, was influenced by predation risk, and the discrepancy between theory and observation most likely reflects shortcomings of the model. These discrepancies indicate that other factors, in addition to exposure time, may be of significance in the perception of predation risk by several (or all) of the species studied. Of particular importance may be a distance-dependent probability of escaping attack. Other results indicate that predation risk may influence handling times via aspects of the digestive process.


Development of the mesencephalic and diencephalic catecholamine systems in human fetuses: uptake and release of catecholamines in vitro.
Development of catecholamine (CA) systems of the ventral mesencephalon and diencephalon were studied in human fetuses at age 6, 8, 10 and 12 weeks, evaluating the CA specific uptake and K(+)-stimulated release with the isotopic biochemical technique. In the mesencephalon, the [3H]dopamine (DA) uptake was detected as early as 6 weeks, suggesting the existence of either CA neurons or fibers. This was followed by gradual increase of the [3H]DA uptake up to 10 weeks and a subsequent fall at 12 weeks. In the diencephalon, the uptake was first observed at 8 weeks, followed by its decrease at 10 weeks and subsequent increase at 12 weeks. The dynamic uptake is considered as a manifestation of the continuous differentiation of CA neurons and sprouting of CA fibers. In contrast to uptake, no CA release was detected in response to membrane depolarization in the diencephalon and mesencephalon at any age studied, suggesting a timing dissociation between the onset of the CA uptake and K(+)-provoked release in the course of neuron differentiation in human fetuses.


Development of a biomarker of efficacy in second-line treatment for lymphangioma of the tongue: a pilot study.
Lymphangioma of the tongue is a rare lymphatic malformation, and various authors have reported the successful use of sirolimus for its treatment. However, the safety of sirolimus in children needs further evaluation so that those who do not respond are not necessarily exposed to its potential adverse effects. We hypothesised that assessment of lymphangiogenesis can be used to predict whether the patient will respond to sirolimus, so we organised a prospective study after ethics committee approval had been given. After clinical and histological diagnoses of lymphangioma of the tongue had been confirmed, 16 patients were given sirolimus 0.8mg/day in three divided doses. Clinical response was assessed and compared with lymphatic microvessel density (LMVD), which was calculated immunohistochemically using the monoclonal antibody D2-40 as the lymphatic endothelial marker. Nine patients responded well, five partially, and two failed to respond. Mean (SD) LVD among the good responders was 21.00 (3.74), whereas among non-responders it was 8.00 (4.24). There was a significant difference in mean LVD between good responders, partial responders, and non-responders (p=0.04). Sirolimus is effective in treating children with lymphangioma of the tongue, and lymphangiogenesis is a useful therapeutic predictive marker.


Effects of manipulation of plant carbon nutrient balance on tall goldenrod resistance to a gallmaking herbivore.
Ramets from six Solidago altissima clones of known resistance to the stem gallmaker Eurosta solidaginis were grown with and without supplemental nutrients. In a greenhouse experiment, mated female Eurosta were allowed to oviposit in ramets that were subsequently grown through flowering and then harvested to determine biomass allocation. Supplemental nutrients increased plant biomass but did not affect resistance to this gallmaking herbivore. This result does not conform to the plant carbon/nutrient balance hypothesis which predicts that enhanced mineral nutrition will indirectly cause a reduction in carbon-based defensive chemistry. Our results indicate a strong genetic basis to ball gallmaker resistance since modification of host phenotype did not influence susceptibility. We suggest that evaluating the degree of genotypic or environmental control of plant resistance will be especially helpful in clarifying the patterns of defensive chemical responses.


Contact dermatitis to hair dyes in a Danish adult population: an interview-based study.
Contact allergy to hair dye ingredients is a well-known entity seen both in consumers using hair dyes and among hairdressers with occupational contact dermatitis. Surveys show that consumers with even severe adverse skin reactions to hair dyes only rarely contact the healthcare services. The frequency of hair dye-induced skin reactions in the consumer population is unknown. An epidemiological investigation with the aim of establishing the proportion of hair dye-induced skin reactions was performed in a population-based sample. A representative random sample (n = 4000) was taken of the Danish adult population. Personal interview questions were asked regarding adverse skin reactions to hair dyes, either compatible with a classical allergic eczematous reaction with redness, scaling and itching or a severe allergic reaction with oedema of the forehead and face. The response rate was 65.2%. A total of 18.4% of the male respondents and 74.9% of the female respondents had at some point dyed their hair. The median age at first hair dyeing was 16 years (range 1-80). Adverse skin reactions to hair dyes compatible with an allergic reaction were reported in 5.3% of individuals who had ever used hair dye. Of these, only 15.6% had been in contact with healthcare services after the hair dye reaction. Having had a temporary tattoo was not a significant risk factor for an adverse reaction to hair dyes. The rate of adverse allergic skin reactions to hair dyes was higher than expected from patch-test studies. Only by studying the clinical types of adverse reactions to hair dyes will it be possible to gather a complete epidemiological picture of the nature and extent of the problems related to hair dye ingredients.


Systems approaches to genomic and epigenetic inter-regulation of peptide hormones in stress and reproduction.
The evolution of the organismal stress response and fertility are two of the most important aspects that drive the fitness of a species. However, the integrated regulation of the hypothalamic pituitary adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes has been traditionally thwarted by the complexity of these systems. Pepidergic signalling systems have emerged as critical integrating systems for stress and reproduction. Current high throughput systems approaches are now providing a detailed understanding of peptide signalling in stress and reproduction. These approaches were dependent upon a long history of discovery aimed at the structural characterization of the associated molecular components. The combination of comparative genomics, microarray and epigenetic studies has led not only to a much greater understanding of the integration of stress and reproduction but also to the discovery of novel physiological systems. Recent epigenomic approaches have similarly yielded a new level of complexity in the interaction of these physiological systems. Together, such studies have provided a greater understanding of the effects of stress and reproduction.


[Mononucleosis syndrome and thrombocytopenic purpura in Q fever (Rickettsia burneti)].
Case of a patient with a mononucleosis syndrome and thrombocytopenic purpura during Q Fever. This etiology could lead to a systematic search for a rickettsial cause for such a symptomatology with a negative Paul-Bunnell-Davidson reaction.


Pillar[5]arene-Derived Terpyridinepalladium(II) Complex: Synthesis, Characterization, and Application in Green Catalysis.
Metal nanoparticle catalysts have attracted great interest because they possess high surface-to-volume ratios and exhibit a very large number of catalytically active sites per unit area. However, high surface-to-volume ratios will induce nanoparticle aggregates during the catalytic reactions, making them lose their catalytic activity. In this work, a monoterpyridine-unit-functionalized pillar[5]arene (TP5) was synthesized successfully, which can be used as anchoring sites for the controllable preparation of well-dispersed palladium nanoparticles [TP5/Pd(0) NPs]. The as-prepared TP5/Pd(0) NPs were fully characterized by X-ray photoelectron spectroscopy, transmission electron microscopy, and powder X-ray diffraction. Importantly, the ultrafine TP5/Pd(0) NPs are found to be excellent and reusable catalysts for the reduction of nitrophenols in aqueous solution.


Vaccination of hamsters against experimental infection with Borrelia burgdorferi.
Vaccination of Syrian hamsters with a single dose of 50 micrograms to 100 micrograms dry weight of a whole cell preparation of Borrelia burgdorferi provided 75% to 86% protection against infection.


Medication therapy of high-dose methotrexate: An evidence-based practice guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.
A lot of medication risks related to high-dose methotrexate (HDMTX) therapy still remain to be identified and standardized. This study aims to establish an evidence-based practice guideline for individualized medication of HDMTX. The practice guideline was launched by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. The guideline was developed following the WHO handbook for guideline development and the methodology of evidence-based medicine (EBM). The guideline was initially registered in the International Practice Guidelines Registry Platform (IPGRP-2017CN021). Systematic reviews were conducted to synthesize available evidence. A multicentre cross-sectional study was conducted using questionnaires to evaluate patients' perception and willingness concerning individualized medication of HDMTX. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to rate the quality of evidence and to grade the strength of recommendations. Multidisciplinary working groups were included in this guideline, including clinicians, pharmacists, methodologists, pharmacologists and pharmacoeconomic specialists. A total of 124 patients were involved to integrate patient values and preferences. Finally, the guideline presents 28 recommendations, regarding evaluation prior to administration (renal function, liver function, pleural effusion, comedications, genetic testing), pre-treatment and routine dosing regimen, therapeutic drug monitoring (necessity, method, timing, target concentration), leucovorin rescue (initial timing, dosage regimen and optimization), and management of toxicities. Of these, 12 are strong recommendations. We developed an evidence-based practice guideline with respect to HDMTX medication using a rigorous and multidisciplinary approach. This guideline provides comprehensive and practical recommendations involving the whole process of HDMTX administration to health care providers.


Spatial spread of infectious diseases with conditional vector preferences.
We explore the spatial spread of vector-borne infections with conditional vector preferences, meaning that vectors do not visit hosts at random. Vectors may be differentially attracted toward infected and uninfected hosts depending on whether they carry the pathogen or not. The model is expressed as a system of partial differential equations with vector diffusion. We first study the non-spatial model. We show that conditional vector preferences alone (in the absence of any epidemiological feedback on their population dynamics) may result in bistability between the disease-free equilibrium and an endemic equilibrium. A backward bifurcation may allow the disease to persist even though its basic reproductive number is less than one. Bistability can occur only if both infected and uninfected vectors prefer uninfected hosts. Back to the model with diffusion, we show that bistability in the local dynamics may generate travelling waves with either positive or negative spreading speeds, meaning that the disease either invades or retreats into space. In the monostable case, we show that the disease spreading speed depends on the preference of uninfected vectors for infected hosts, but also on the preference of infected vectors for uninfected hosts under some circumstances (when the spreading speed is not linearly determined). We discuss the implications of our results for vector-borne plant diseases, which are the main source of evidence for conditional vector preferences so far.