Effect of sympathetic autonomic stress from the cold pressor test on left ventricular function in young healthy adults.
There is a dearth of studies investigating the effect of sympathetic activation on left ventricular function. This study aimed to investigate the effect of sympathetic autonomic stress on left ventricular function in young healthy adults. Fifty-six normotensive healthy participants (age 23.55 ± 3.82 years) took part in the study after giving informed consent. After obtaining baseline measurements, heart rate (HR), blood pressure (BP), peripheral saturation of oxygen (SpO2) and left ventricular function (assessed by means of ejection fraction (EF) obtained by transthoracic 2-D echocardiography) were determined before and following sympathetic activation using cold pressor test (CPT). Exposure to CPT led to significant increase (P < 0.0001) in HR (70.4 ± 10.7 bpm to 91.6 ± 14.8 bpm), SBP (118 ± 8 mmHg to 138 ± 14 mmHg) and DBP (71 ± 7 mmHg to 91 ± 11 mmHg). Participants' EDV (101.1 ± 15.8 ml to 104.2 ± 19.3 mL), ESV (38.7 ± 9.1 mL to 40.3 ± 11.6 mL), SpO2 (99.5 ± 0.79% to 99.5 ± 0.77%) and EF (61.9 ± 5.9% to 60.9 ± 6.4%) were only slightly changed (P > 0.05). However, cardiac output (4.3 ± 0.9 L/min to 5.4 ± 1.4 L/min) and cardiac index (3.7 ± 0.8 L/min per m2 to 4.5 ± 1.4 L/min per m2 ) increased significantly (P < 0.0001). We conclude that sympathetic stress induced by cold pressor test has marginal effect on ejection fraction and fractional shortening while increasing cardiac output and cardiac index in young healthy adults.


Semiclassical initial value theory of rotationally inelastic scattering: Some remarks on the phase index in the interaction picture.
This paper deals with the treatment of quantum interferences in the semiclassical initial value theory of rotationally inelastic scattering in the interaction picture. Like many semiclassical methods, the previous approach involves a phase index related to sign changes of a Jacobian whose square root is involved in the calculations. It is shown that replacing the original phase index by a new one extends the range of applicability of the theory. The resulting predictions are in close agreement with exact quantum scattering results for a model of atom-rigid diatom collision involving strong interferences. The developments are performed within the framework of the planar rotor model, but are readily applicable to three-dimensional collisions.


[Contrast analysis on two air fluorine content measurement methods].
To take the two kinds of sampling and measurement methods of air fluorine content in the endemic fluorosis area to carry on the comparison, understanding their difference and inside relation. Sampled 22 households random on the scene in the disease area with two samplers by two methods, at the position of which, at the same time, equidistance, same highness, as close as possible, but not produce interactive effect, to collect 34 of the air sample, and then gained the results by their respective methods of laboratory analysis and statistical analysis. The test of significance between two methods was P > 0.05, the coefficient of correlation was r = 0.7752, the test of significance was P < 0.01, the equation of linear regression between the GB method (X) and the manual method (Y) was Y = 1.1623X + 0.0008, the test of significance of coefficient of regression was P < 0.01. Two kinds of methods had no significant differences. They preset the medium degree positive correlation and a linear regression. The air fluoride in different granularity of suspended particles was not the same. The GB method was more applicable to research of synthesis damage towards the exposing crowd in burning coal fluorine, and manual method was more applicable to research of the damage resulting from the exposing crowd in burning coal fluorine through the breath system. Generally speaking, the results of the manual method was higher than the GB method.


Optimization of adsorptive immobilization of alcohol dehydrogenases.
In this work, a systematic examination of various parameters of adsorptive immobilization of alcohol dehydrogenases (ADHs) on solid support is performed and the impact of these parameters on immobilization efficiency is studied. Depending on the source of the enzymes, these parameters differently influence the immobilization efficiency, expressed in terms of residual activity and protein loading. Residual activity of 79% was achieved with ADH from bakers' yeast (YADH) after optimizing the immobilization parameters. A step-wise drying process has been found to be more effective than one-step drying. A hypothesis of deactivation through bubble nucleation during drying of the enzyme/glass bead suspension at low drying pressure (<45 kPa) is experimentally verified. In the case of ADH from Lactobacillus brevis (LBADH), >300% residual activity was found after drying. Hyperactivation of the enzyme is probably caused by structural changes in the enzyme molecule during the drying process. ADH from Thermoanaerobacter species (ADH T) is found to be stable under drying conditions (>15 kPa) in contrast to LBADH and YADH.


The predictive value of bedside ultrasound to restore spontaneous circulation in patients with pulseless electrical activity: A systematic review and meta-analysis.
The prognosis of pulseless electrical activity is dismal. However, it is still challengable to decide when to terminate or continue resuscitation efforts. The aim of this study was to determine whether the use of bedside ultrasound (US) could predict the restoration of spontaneous circulation (ROSC) in patients with pulseless electrical activity (PEA) through the identification of cardiac activity. This was a systematic review and meta-analysis of studies that used US to predict ROSC. A search of electronic databases (Cochrane Central, MEDLINE, EMBASE) was conducted up to June 2017, and the assessment of study quality was performed with the Newcastle-Ottawa Scale. Statistical analysis was performed with Review Manager 5.3 and Stata 12. Eleven studies that enrolled a total of 777 PEA patients were included. A total of 230 patients experienced ROSC. Of these, 188 had sonographically identified cardiac activity (pseudo-PEA). A meta-analysis showed that PEA patients with cardiac activity on US were more likely to obtain ROSC compared to those with cardiac standstill: risk ratio (RR) = 4.35 (95% confidence interval [CI], 2.20-8.63; p<0,00001) with significant statistical heterogeneity (I2 = 60%). Subgroup analyses were conducted: US evaluation using only on the subxiphoid view: RR = 1.99 (95% CI, 0.79-5.02; p = 0.15); evaluation using various views: RR = 4.09 (95% CI,2.70-6.02; p<0.00001). In cardiac arrest patients who present with PEA, bedside US has an important role in predicting ROSC. The presence of cardiac activity in PEA patients may encourage more aggressive resuscitation.


Infrared spectroscopy of anionic hydrated fluorobenzenes.
We investigate the structural motifs of anionic hydrated fluorobenzenes by infrared photodissociation spectroscopy and density functional theory. Our calculations show that all fluorobenzene anions under investigation are strongly distorted from the neutral planar molecular geometries. In the anions, different F atoms are no longer equivalent, providing structurally different binding sites for water molecules and giving rise to a multitude of low-lying isomers. The absorption bands for hexa- and pentafluorobenzene show that only one isomer for the respective monohydrate complexes is populated in our experiment. For C6F6.-H2O, we can assign these bands to an isomer where water forms a weak double ionic hydrogen bond with two F atoms in the ion, in accord with the results of Bowen et al. [J. Chem. Phys. 127, 014312 (2007), following paper.] The spectroscopic motif of the binary complexes changes slightly with decreasing fluorination of the aromatic anion. For dihydrated hexafluorobenzene anions, several isomers are populated in our experiments, some of which may be due to hydrogen bonding between water molecules.


Subtype-specific plasma signatures of platelet-related protein releasate in acute pulmonary embolism.
There is evidence that plasma protein profiles differ in the two subtypes of pulmonary embolism (PE), isolated PE (iPE) and deep vein thrombosis (DVT)-associated PE (DVT-PE), in the acute phase. The aim of this study was to determine specific plasma signatures for proteins related to platelets in acute iPE and DVT-PE compared to isolated DVT (iDVT). Within the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism (GMP-VTE) Project, a multicenter prospective cohort study of 693 confirmed VTE cases, a highly sensitive targeted proteomics approach based on dual-antibody proximity extension assay was applied. LASSO-regularized logistic regression analysis selected 33 and 30 of 135 platelet-related candidate proteins in iPE and DVT-PE vs. iDVT, respectively. All regulated proteins were well associated with six prominently released platelet proteins and the majority showed specificity for iPE and DVT-PE compared to iDVT. While iPE-specific proteins were assigned to be predominantly released via shedding mechanisms and extracellular vesicles, granule secretion was identified as a major release mechanism assigned to DVT-associated PE-specific proteins. Network analysis demonstrated three interconnected clusters of specifically regulated proteins in iPE linked to immunoreceptor signaling, pathogen clearance and chemotaxis, whereas for DVT-associated PE one cluster linked to tissue remodeling and leukocyte trafficking. Machine learning-based analysis reveals specific plasma signatures and differential release mechanisms of proteins related to platelets in acute iPE and DVT-associated PE. These data suggest that the platelet protein releasate contributes to the differential regulation of plasma proteins in acute PE compared to iDVT, which may be associated with different platelet activation patterns.


Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus.
To evaluate the effects of targeting Ikaros and Aiolos by cereblon modulator iberdomide on the activation and differentiation of B-cells from patients with systemic lupus erythematosus (SLE). CD19+ B-cells isolated from the peripheral blood of patients with SLE (n=41) were cultured with TLR7 ligand resiquimod ±IFNα together with iberdomide or control from day 0 (n=16). Additionally, in vitro B-cell differentiation was induced by stimulation with IL-2/IL-10/IL-15/CD40L/resiquimod with iberdomide or control, given at day 0 or at day 4. At day 5, immunoglobulins were measured by ELISA and cells analysed by flow cytometry. RNA-Seq was performed on fluorescence-activated cell-sorted CD27-IgD+ naïve-B-cells and CD20lowCD27+CD38+ plasmablasts to investigate the transcriptional consequences of iberdomide. Iberdomide significantly inhibited the TLR7 and IFNα-mediated production of immunoglobulins from SLE B-cells and the production of antinuclear antibodies as well as significantly reducing the number of CD27+CD38+ plasmablasts (0.3±0.18, vehicle 1.01±0.56, p=0.011) and CD138+ plasma cells (0.12±0.06, vehicle 0.28±0.02, p=0.03). Additionally, treatment with iberdomide from day 0 significantly inhibited the differentiation of SLE B-cells into plasmablasts (6.4±13.5 vs vehicle 34.9±20.1, p=0.013) and antibody production. When given at later stages of differentiation, iberdomide did not affect the numbers of plasmablasts or the production of antibodies; however, it induced a significant modulation of gene expression involving IKZF1 and IKZF3 transcriptional programmes in both naïve B-cells and plasmablasts (400 and 461 differentially modulated genes, respectively, false discovery rate<0.05). These results demonstrate the relevance of Ikaros and Aiolos as therapeutic targets in SLE due to their ability to modulate B cell activation and differentiation downstream of TLR7.


Site-Directed Mutagenesis of Large Biosynthetic Gene Clusters via Oligonucleotide Recombineering and CRISPR/Cas9 Targeting.
Genetic engineering of natural product biosynthetic gene clusters represents an attractive approach to access new and complex bioactive small molecules. However, due to the large number and size of some genes involved in specialized metabolism, notably those encoding modular polyketide synthase and nonribosomal peptide synthetase megaproteins, it remains difficult to introduce precise genetic mutations to probe domain activity or alter chemical product formation. Here, we report the development and validation of a robust method combining oligonucleotide recombineering and CRISPR/Cas9 targeting for rapid site-directed mutagenesis of cloned pathways, which can be directly transferred to a heterologous host for expression. We rapidly generated 12 point mutations and identified several important determinants of successful mutagenesis, including the protospacer/PAM sequence and presence of regions of local homology. Our approach may be broadly applicable for researchers interested in probing natural product biosynthesis or performing pathway engineering.


Regulation of kallikrein-related peptidases in the skin - from physiology to diseases to therapeutic options.
Kallikrein-related peptidases (KLKs) constitute a family of 15 highly conserved serine proteases, which show a tissue-specific expression profile. This made them valuable tumour expression markers. It became evident that KLKs are involved in many physiological processes like semen liquefaction and skin desquamation. More recently, we have learnt that they are involved in many pathophysiological conditions and diseases making them promising target of therapeutic intervention. Therefore, regulation of KLKs raised the interest of numerous reports. Herein, we summarise the current knowledge on KLKs regulation with an emphasis on skin-relevant KLKs regulation processes. Regulation of KLKs takes place on the level of transcription, on protease activation and on protease inactivation. A variety of protease inhibitors has been described to interact with KLKs including the irreversible serine protease inhibitors (SERPINs) and the reversible serine protease inhibitors of Kazal-type (SPINKs). In an attempt to integrate current knowledge, we propose that KLK regulation has credentials as targets for therapeutic intervention.


Acute cysticercal meningitis--missed diagnosis.
Neurocysticercosis is the commonest CNS parasitic disease worldwide but cysticercal meningoencephalitis is relatively rare, especially in Indian patients. We herein report a girl with cysticercal meningitis that was initially not suspected and later diagnosed on the basis of cerebrospinal fluid (CSF) eosinophilia. The need for CSF examination with wright-giemsa staining to avoid missing CSF eosinophilia is discussed.


Presynaptic alpha 2-adrenoceptor mediated regulation of norepinephrine release in perfused mesenteric vasculatures in young and adult spontaneously hypertensive rats.
The present study was designed to evaluate the role of the presynaptic alpha 2-adrenoceptor in the pathogenesis of hypertension. Norepinephrine overflow during sympathetic nerve stimulation and its changes by presynaptic alpha 2-adrenoceptor inhibition were examined in the perfused mesenteric vasculatures of young and adult spontaneously hypertensive rats (SHR) compared with age-matched Wistar Kyoto rats (WKY). Electrical sympathetic nerve stimulation caused significantly greater overflow of endogenous norepinephrine from the adrenergic nerve terminals in young SHR than in age-matched WKY. Yohimbine, an alpha 2-adrenoceptor blocking agent, facilitated norepinephrine overflow from the adrenergic nerve terminals. The effects of yohimbine on norepinephrine overflow and pressor responses to electrical nerve stimulation were less in young SHR than in age-matched WKY. Norepinephrine overflow in adult SHR was similar to that in adult WKY, and differences in the effect of yohimbine on norepinephrine overflow between SHR and WKY were not marked at this chronic stage. These results suggest that enhanced norepinephrine overflow in the mesenteric vasculatures can be observed only in young SHR; this may be due in part to an impaired negative feed-back mechanism on the nerve terminals by presynaptic alpha 2-adrenoceptors.


Development of Porous Photopolymer Resin-SWCNT Produced by Digital Light Processing Technology Using for Bone Femur Application.
Although bone tissue has the unique characteristic of self-repair in fractures, bone grafting is needed in some situations. The synthetic substances that are used in such situations should bond to the porous bones, be biocompatible and biodegradable, and do not stimulate the immune responses. Biomaterial engineering is the science of finding and designing novel products. In principle, the most suitable biodegradable matrix should have adequate compressive strength of more than two megapascals. At this degradation rate, the matrix can eventually be replaced by the newly formed bone, and the osteoprogenitor cells migrate into the scaffold. This study aimed to evaluate the fabrication of a scaffold made of polymer-ceramic nanomaterials with controlled porosity resembling that of spongy bone tissue. A compound of resin polymer, single-walled carbon nanotube (SWCNT) as reinforcement, and hydroxyapatite (HA) were dissolved using an ultrasonic and magnetic stirrer. A bio-nano-composite scaffold model was designed in the SolidWorks software and built using the digital light processing (DLP) method. Polymer-HA scaffolds with the solvent system were prepared with similar porosity to that of human bones. HA-polymer scaffolds had a random irregular microstructure with homogenizing porous architecture. The SWCNT improved the mechanical properties of the sample from 25 MPa to 36 MPa besides having a proper porosity value near 55%, which can enhance the transformation and absorption of protein in human bone. The combined bio-nanocomposite had a suitable porous structure with acceptable strength that allowed it to be used as a bone substitute in orthopedic surgery.


BEZ235 (PIK3/mTOR inhibitor) Overcomes Pazopanib Resistance in Patient-Derived Refractory Soft Tissue Sarcoma Cells.
Although pazopanib treatment has become the standard chemotherapy in salvage setting for metastatic sarcoma patients, most patients progress after pazopanib treatment in 4 to 6 months. After failure to pazopanib, patients have limited options for treatment. Therefore, subsequent therapy in patients who failed to pazopanib is urgently needed and the use of patient derived cells or patient derived tumors for accompanying testing with various pharmacological inhibitors could offer additional treatment options for these patients. Patient derived tumor cells were collected from ascites at the time of progression to pazopanib and a 13-drug panel was tested for drug sensitivity. We confirmed the results using in vitro cell viability assay and immunoblot assay. We also performed the genomic profiling of PDX model. The growth of patient derived tumor cells was significantly reduced by exposure to 1.0 μM AZD2014 compared with control (control versus AZD2014, mean growth = 100.0% vs 16.04%, difference = 83.96%, 95% CI = 70.01% to 97.92%, P = .0435). Similarly, 1.0 μM BEZ235 profoundly inhibited tumor cell growth in vitro when compared to control (control versus BEZ235, mean growth = 100.0% vs 7.308%, difference = 92.69%, 95% CI = 78.87% to 106.5%, P < .0001). Despite the presence of CDK4 amplification in the patient-derived tumor cells, LEE011 did not considerably inhibit cell proliferation when compared with control (control vs LEE011, mean growth = 100.0% vs 80.23%, difference = 19.77%, 95% CI = 1.828% to 37.72%, P = .0377). The immunoblot analysis showed that BEZ235 treatment decreased pAKT, pmTOR and pERK whereas AZD2014 decreased only pmTOR. Taken together, upregulation of mTOR/AKT pathway in sarcoma patient derived cells was considerably inhibited by the treatment of AZD2014 and BEZ235 with downregulation of AKT pathway (greater extent for BEZ235). These molecules may be considered as treatment option in STS patient who have failed to pazopanib in the context of clinical trials.


Graphene oxide-modified electrodes for sensitive determination of diethylstilbestrol.
This paper reports an electrochemical sensor fabricated with graphene oxide (GO) modified on a chitosan-coated glassy carbon electrode (GO-CS/GCE) and its application for the detection of diethylstilbestrol (DES). It was observed that the effective electrochemical surface area of the GO modified electrode was nearly 10 times that of the bare GCE. This could be used to explain the results that the oxidation peak current of DES on the GO-CS/GCE was much larger than on the bare GCE. Under optimized conditions, the prepared electrode could be used to electrochemically detect DES according to the oxidation of the DES. Based on the technique of differential pulse voltammetry and the accumulation of DES on GO modified electrodes, the calibration curve for DES determination could be obtained with a linear range of 1.5 × 10(-8)-3.0 × 10(-5) M and an estimated detection limit of 3.0 × 10(-9) M (S/N = 3). The feasibility of the developed electrode for tablet sample analysis was investigated. Our investigation revealed that GO could significantly improve the analytical performance of electrochemical sensors.


The unholy trinity: taxonomy, species delimitation and DNA barcoding.
Recent excitement over the development of an initiative to generate DNA sequences for all named species on the planet has in our opinion generated two major areas of contention as to how this 'DNA barcoding' initiative should proceed. It is critical that these two issues are clarified and resolved, before the use of DNA as a tool for taxonomy and species delimitation can be universalized. The first issue concerns how DNA data are to be used in the context of this initiative; this is the DNA barcode reader problem (or barcoder problem). Currently, many of the published studies under this initiative have used tree building methods and more precisely distance approaches to the construction of the trees that are used to place certain DNA sequences into a taxonomic context. The second problem involves the reaction of the taxonomic community to the directives of the 'DNA barcoding' initiative. This issue is extremely important in that the classical taxonomic approach and the DNA approach will need to be reconciled in order for the 'DNA barcoding' initiative to proceed with any kind of community acceptance. In fact, we feel that DNA barcoding is a misnomer. Our preference is for the title of the London meetings--Barcoding Life. In this paper we discuss these two concerns generated around the DNA barcoding initiative and attempt to present a phylogenetic systematic framework for an improved barcoder as well as a taxonomic framework for interweaving classical taxonomy with the goals of 'DNA barcoding'.


Management of MANEC of the colon and rectum: A comprehensive review of the literature.
Mixed adeno-neuroendocrine carcinoma (MANEC) is a rare pathological diagnosis recently acknowledged by the World Health Organization in 2010. MANEC is a neoplasm characterized by significant histological heterogeneity and is characterized by the simultaneous presence of both adenocarcinomatous and neuroendocrine differentiation; their definition includes each component found in at least 30% of the tumor. Colorectal MANEC constitutes an uncommon type of malignant tumor. The true prevalence of colorectal MANEC has not been precisely defined and published studies are limited to case reports and small case series. The aim of the present review was to accumulate the existing evidence on colorectal MANEC with special attention to the clinicopathological characteristics, management and survival rates of patients diagnosed with this malignancy. A total of 20 studies (16 case reports and 4 retrospective cohorts) reported outcomes for patients with colorectal MANEC and were finally considered eligible for analysis. The results of the present study show that patients with early stage MANEC have more favorable survival compared to those diagnosed in advanced stages. Due to its neuroendocrine nature, which is characterized by rapid progression, MANEC is diagnosed in advanced stages in the majority of cases and thus potentially explains the poor survival rates. Because of its aggressive nature and high recurrence rate, adjuvant chemotherapy constitutes a critical part of the treatment and significantly improves survival. Further larger studies are needed in order to establish guidelines for the treatment of these rare lesions.


Lipase active-site-directed anchoring of organometallics: metallopincer/protein hybrids.
The work described herein presents a strategy for the regioselective introduction of organometallic complexes into the active site of the lipase cutinase. Nitrophenol phosphonate esters, well known for their lipase inhibitory activity, are used as anchor functionalities and were found to be ideal tools to develop a single-site-directed immobilization method. A small series of phosphonate esters, covalently attached to ECE "pincer"-type d8-metal complexes through a propyl tether (ECE=[C6H3(CH2E)(2)-2,6]-; E=NR2 or SR), were designed and synthesized. Cutinase was treated with these organometallic phosphonate esters and the new metal-complex/protein hybrids were identified as containing exactly one organometallic unit per protein. The organometallic proteins were purified by membrane dialysis and analyzed by ESI-mass spectrometry. The major advantages of this strategy are: 1) one transition metal can be introduced regioselectively and, hence, the metal environment can potentially be fine-tuned; 2) purification procedures are facile due to the use of pre-synthesized metal complexes; and, most importantly, 3) the covalent attachment of robust organometallic pincer complexes to an enzyme is achieved, which will prevent metal leaching from these hybrids. The approach presented herein can be regarded as a tool in the development of regio- and enantioselective catalyst as well as analytical probes for studying enzyme properties (e.g., structure) and, hence, is a "proof-of-principle design" study in enzyme chemistry.


Experimental implementation of the gyrator transform.
The gyrator transform (GT) promises to be a useful tool in image processing, holography, beam characterization, mode transformation, and quantum information. We introduce what we believe to be the first flexible optical experimental setup that performs the GT for a wide range of transformation parameters. The feasibility of the proposed scheme is demonstrated on the gyrator transformation of Hermite-Gaussian modes. For certain parameters the output mode corresponds to the Laguerre-Gaussian one.


[Comparative analysis of drug resistant mutations in the reverse transcriptase domain of hepatitis B virus covalently closed circular DNA and the viral relax circle DNA].
To establish a method for detection of reverse transcriptase region of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), and to compare the pattern and frequency of drug-resistant mutations in the region between intrahepatic HBV cccDNA and serum HBV relax circle DNA (rcDNA). HBV DNA were extracted from liver biopsy tissues of 20 patients with chronic hepatitis B. The RT region of HBV cccDNA was amplified by rolling circle amplification (RCA) followed by polymerase chain reaction (PCR) mediated by a pair of primers spanning across the gap region of HBV genome. The RT region of serum HBV rcDNA from the same patient was amplified by nested-PCR. The PCR products were directly sequenced and analyzed by Vector NTI Suite 8.0 and chromaslite 201 software. x2 test was used for statistical significance analysis of drug-resistant mutation occurrences between the HBV cccDNA and rcDNA. The RT regions of HBV cccDNA were successfully amplified from liver tissues of all enrolled patients using the RCA plus PCR assay. Simultaneously, HBV the RT regions of rcDNA were amplified from these patients serum samples. Sequence analysis showed that the drug-resistant mutations were significantly more frequently detected in HBV rcDNA (40%) than in HBV cccDNA (10%) (P<0.05). Different mutational patterns were observed between the HBV cccDNA and rcDNA in a few cases. The RCA in combination with PCR is a practical method for the detection of drug-resistant mutation in the RT region of HBV cccDNA. Drug-resistant mutational patterns could be discrepant between HBV cccDNA and rcDNA.


Molecular Functions of Hydrogen Sulfide in Cancer.
Hydrogen sulfide (H2S) is a gasotransmitter that exerts a multitude of functions in both physiologic and pathophysiologic processes. H2S-synthesizing enzymes are increased in a variety of human malignancies, including colon, prostate, breast, renal, urothelial, ovarian, oral squamous cell, and thyroid cancers. In cancer, H2S promotes tumor growth, cellular and mitochondrial bioenergetics, migration, invasion, angiogenesis, tumor blood flow, metastasis, epithelia-mesenchymal transition, DNA repair, protein sulfhydration, and chemotherapy resistance Additionally, in some malignancies, increased H2S-synthesizing enzyme expression correlates with a worse prognosis and a higher tumor stage. Here we review the role of H2S in cancer, with an emphasis on the molecular mechanisms by which H2S promotes cancer development, progression, dedifferentiation, and metastasis.


Development, characterization and application of monoclonal antibodies against Brazilian Dengue virus isolates.
Dengue is the most prevalent human arboviral disease. The morbidity related to dengue infection supports the need for an early, quick and effective diagnostic test. Brazil is a hotspot for dengue, but no serological diagnostic test has been produced using Brazilian dengue virus isolates. This study aims to improve the development of immunodiagnostic methods for dengue virus (DENV) detection through the production and characterization of 22 monoclonal antibodies (mAbs) against Brazilian isolates of DENV-1, -2 and -3. The mAbs include IgG2bκ, IgG2aκ and IgG1κ isotypes, and most were raised against the envelope or the pre-membrane proteins of DENV. When the antibodies were tested against the four DENV serotypes, different reactivity patterns were identified: group-specific, subcomplex specific (DENV-1, -3 and -4 and DENV-2 and -3) and dengue serotype-specific (DENV-2 or -3). Additionally, some mAbs cross-reacted with yellow fever virus (YFV), West Nile virus (WNV) and Saint Louis encephalitis virus (SLEV). None of the mAbs recognized the alphavirus Venezuelan equine encephalitis virus (VEEV). Furthermore, mAbs D3 424/8G, D1 606/A12/B9 and D1 695/12C/2H were used to develop a capture enzyme-linked immunosorbent assay (ELISA) for anti-dengue IgM detection in sera from patients with acute dengue. To our knowledge, these are the first monoclonal antibodies raised against Brazilian DENV isolates, and they may be of special interest in the development of diagnostic assays, as well as for basic research.


Evaluation of sustained grip strength for a stroke patient with a mild paresis.
The purpose of this study was to investigate whether a sustained grip strength test is workable as an accurate assessment of activity limitation related to muscle weakness of the paretic hands of stroke patients with mild pareses. Sixty-one stroke patients with mild pareses participated in this study. The maximal grip strength and an ability to sustain grip strength were examined with the Sustained Grip Strength Test. The latter ability was measured by the sustained period of the maximal grip strength (a period that exhibited more than 80% of the peak force during a six-seconds trial). The activity limitation of squeezing an object was evaluated in four ADL tasks, and the difficulties were rated according to three scores. We found that there was a significant positive relationship between the degree of the task difficulty and the maximal grip strength for paretic hands whose sustained period was over three sec, in all four assessments (p < 0.05). However, for paretic hands whose sustained period was under three sec, no such relationship was found. Consequently, measuring both the maximal grip strength and the sustained period was needed to assess accurately an activity limitation related to muscle weakness of the paretic hands of stroke patients with mild pareses.


Multiple myeloma patients in long-term complete response after autologous stem cell transplantation express a particular immune signature with potential prognostic implication.
The proportion of multiple myeloma patients in long-term complete response (LTCR-MM) for more than 6 years after autologous stem cell transplantation (ASCT) is small. To evaluate whether this LTCR is associated with a particular immune signature, peripheral blood samples from 13 LTCR-MM after ASCT and healthy blood donors (HBD) were analysed. Subpopulations of T-cells (naïve, effector, central memory and regulatory), B-cells (naïve, marginal zone-like, class-switched memory, transitional and plasmablasts) and NK-cells expressing inhibitory and activating receptors were quantified by multiparametric flow cytometry (MFC). Heavy/light chains (HLC) were quantified by nephelometry. The percentage of CD4+ T-cells was lower in patients, whereas an increment in the percentage of CD4+ and CD8+ effector memory T-cells was associated with the LTCR. Regulatory T-cells and NK-cells were similar in both groups but a particular redistribution of inhibitory and activating receptors in NK-cells were found in patients. Regarding B-cells, an increase in naïve cells and a corresponding reduction in marginal zone-like and class-switched memory B-cells was observed. The HLC values were normal. Our results suggest that LTCR-MM patients express a particular immune signature, which probably reflects a 'high quality' immune reconstitution that could exert a competent anti-tumor immunological surveillance along with a recovery of the humoral immunity.


Intense myelofibrosis in a child: unusual result of EBV-associated hemophagocytic lymphohistiocytosis.
A previously healthy 12-year-old girl was admitted to the intensive care unit with severe pulmonary bleeding. Her history revealed that she had suffered from high fever, fatigue, sore throat, myalgia and generalized rash for two weeks. Physical examination revealed hepatosplenomegaly. Laboratory investigation showed pancytopenia associated with unusual high levels of serum ferritin, triglyceride and lactate dehydrogenase (LDH) and low fibrinogen levels. Apparent hemophagocytosis was seen in bone marrow aspiration. Bone marrow biopsy revealed myelofibrosis, and confirmed hemophagocytosis. IgM for Epstein-Barr virus (EBV) viral capsid antigen was found to be positive. She received chemotherapy for 10 days according to hemophagocytic lymphohistiocytosis (HLH)-2004 treatment protocol, since the symptoms persisted despite supportive therapy and intravenous immunoglobulin (IVIG) administration. However, the clinical status and laboratory findings did not respond to treatment and she died from severe pulmonary bleeding associated with prolonged ventilator support and sepsis. Intense myelofibrosis, which is reported rarely, particularly in patients with EBV-related HLH, contributed to this fatal prognosis.


Plasminogen activation is stimulated by prion protein and regulated in a copper-dependent manner.
Prion diseases are associated with the conversion of the normal prion protein, PrP(C), to the infectious disease form PrP(Sc). Discrimination between these isoforms would significantly enhance diagnosis of these diseases, and it has recently been reported that PrP(Sc) is specifically recognized by the serine protease zymogen plasminogen (Fischer et al. (2000) Nature 408, 479). Here we have tested the hypothesis that PrP is a regulator of the plasminogen activation system. The effect of recombinant PrP, either containing copper (holo-PrP) or devoid of it (apo-PrP), on plasminogen activation by both uPA and tPA was determined. PrP had no effect on plasminogen activation by uPA. By contrast, the activity of tPA was stimulated by up to 280-fold. This was observed only with the apo-PrP isoforms. The copper-binding octapeptide repeat region of PrP was involved in the effects, as a mutant lacking this region failed to stimulate plasminogen activation, although a synthetic peptide corresponding to this region was unable to stimulate tPA activity. Competition experiments demonstrated that, in addition to plasminogen binding, the stimulation required a high-affinity interaction between tPA and PrP (K(d) < 2.5 nM). Kinetic analysis revealed a template mechanism for the stimulation, suggesting independent binding sites for tPA and plasminogen. Lack of copper-binding may be an early event in the conversion of PrP(C) to PrP(Sc), and our data therefore suggest that tPA-catalyzed plasminogen activation may provide the basis for a sensitive detection system for the early stages of prion diseases and also play a role in the pathogenesis of these diseases.


CRISPR-Cas9 engineering in the hybrid yeast Zygosaccharomyces parabailii can lead to loss of heterozygosity in target chromosomes.
The hybrid yeast Zygosaccharomyces parabailii holds potential as a cell factory mainly because of its robustness in withstanding stressors that often characterize bio-based processes. However, a complex genome and a lack of gene editing tools hinder the capacity to engineer this yeast. In this work, we developed a CRISPR-Cas9 gene editing system for Z. parabailii that allows simultaneous disruption or deletion of both alleles of a gene. We evaluated four different gRNA expression systems consisting of combinations of tRNAs, tRNA and ribozyme or ribozymes as self-cleaving flanking elements and established that the most efficient systems used an RNA Pol II promoter followed by a 5'tRNA flanking the gRNA. This gRNA system was then used to construct a strain of Z. parabailii in which both alleles of DNL4 were inactivated and so relied on homologous recombination to repair double-stranded breaks. Our system can be used for gene inactivation in a wild-type strain and precise deletion with marker insertion in a dnl4 mutant. In some cases, we observed inter-chromosomal recombination around the site of the DSB that could cause loss of heterozygosity through gene conversion or deletion. Although an additional aspect that needs to be monitored during strain engineering, this phenomenon also offers opportunities to explore genome plasticity in hybrid yeasts.


Capsanthin, a Plant-Derived Xanthophyll: a Review of Pharmacology and Delivery Strategies.
Capsanthin, a brightly orange-red-coloured pigment responsible for the peculiar red colour of paprika fruits (Capsicum annuum), belongs to xanthophylls, a class of oxygen-containing carotenoids. The characteristic chemical structure of capsanthin containing a keto group in conjunction with a long chain of 11 conjugated dienes is responsible for its strong radical scavenging and singlet oxygen quenching ability. Chemopreventive, antitumour, skin photo-protective, anti-inflammatory, and antidiabetic activities demonstrated by capsanthin are a consequence of its potent antioxidant action. Anti-obesity, anti-adipogenic, and antihyperlipidaemic activities are some of the more important features of capsanthin. With natural origin, bright red colour, and array of health benefits, capsanthin has a potential to be translated into a commercial cosmeceutical, nutraceutical, and/or pharmaceutical. However, the very low aqueous solubility of capsanthin is responsible for its highly variable and poor oral bioavailability. Moreover, its susceptibility to degradation due to heat, light, oxygen, and moisture poses challenges in the development of stable formulations for this otherwise meritorious compound. The current review presents various pharmacological activities of capsanthin and their underlying mechanisms. The review further discusses hitherto explored formulation strategies to improve solubility and stability of capsanthin. Graphical abstract.


Somatic VHL alteration and its impact on prognosis in patients with clear cell renal cell carcinoma.
Somatic inactivation of the von Hippel-Lindau (VHL) gene is the most frequent genetic event observed in clear cell renal cell carcinoma (CC-RCC). However, the prognostic relevance of somatic VHL alteration and its target, hypoxia inducible factor (HIF)-1alpha has not been defined. We investigated the genetic changes in the VHL gene and HIF-1alpha and studied their clinical implications in patients with sporadic CC-RCC. Patients who underwent nephrectomy were eligible if they had pathologically confirmed CC-RCC not associated with VHL disease or familial RCC. Tumor tissues were selected from paraffin blocks on the basis of hematoxylin and eosin (H&E)-stained sections. Polymerase chain reaction-single strand conformation polymorphism analysis was performed to detect VHL mutations and genetic changes in HIF-1alpha, which were followed by automated direct sequencing. VHL hypermethylation was examined by methylation-specific PCR. A total of 56 patients were enrolled and somatic VHL alterations were detected in 16 patients (29%); intragenic mutation in eight, hypermethylation in five, both alterations in three. The mutation types were missense in five patients, silent in three, nonsense in two, and frameshift in one. Somatic VHL alterations were not significantly associated with progression-free survival (PFS) or overall survival (OS). However, patients with 'loss-of-function' VHL mutation showed significantly decreased PFS (P=0.016) and OS (P=0.046). Although the association between VHL alteration and response to immunotherapy was not significant (P=0.486), patients with missense mutation seem to have better response to immunotherapy. The Pro582Ser change in HIF-1alpha was detected in six patients (11%) and was positively correlated with the development of metastases (P=0.023). This study did not show an association between somatic VHL alteration and prognosis in patients with sporadic CC-RCC. However, it suggests that the therapeutic and prognostic implication of somatic VHL alteration may be different according to the mutational subtype and that the Pro582Ser change in HIF-1alpha may contribute to the development of metastases.


Physical activity practice during COVID-19 pandemic in patients with intermittent claudication.
To describe physical activity habits and barriers for physical activity practice in patients with peripheral artery disease and claudication symptoms during Coronavirus 2019 (COVID-19) pandemic. In this cross-sectional survey study, 127 patients with peripheral artery disease (59.8% men; 68±9 years old; and 81.9% had the peripheral artery disease diagnosis ≥5 years old) were included. The physical activity habits and barriers for physical activity practice were assessed through telephone interview using a questionnaire with questions related to: (a) COVID-19 personal care; (b) overall health; (c) physical activity habits; (d) for those who were inactive, the barriers for physical activity practice. Only 26.8% of patients reported practicing physical activity during the COVID-19 pandemic. Exercise characteristics more common among these patients include walking, performed at least 5 days a week, during 31-60 min at light intensity. In contrast, among physically inactive patients, pain, injury or disability (55%), the COVID-19 pandemic (50%), the need to rest due to leg pain (29%), and lack of energy (27%) were the most frequent barriers to physical activity practice. The physical activity level of patients with peripheral artery disease is impacted by the COVID-19 pandemic.


Lipids and all-cause mortality among older adults: a 12-year follow-up study.
This is a 12-year follow-up cohort study with 800 people (60-85 years old). The association between lipid disorders and mortality was analysed by Cox proportional hazard adjusted model. All-cause mortality was considered the dependent variable, and lipid disorders as independent variables: total cholesterol (TC) >200 and <170 mg/dl, HDL-c <35 and 40, LDL-c >100 and 130, and triglycerides (TG) >50. An initial analysis of all subjects was performed and a second was carried out after having excluded individuals with a body mass index (BMI) <20 kg/m² or mortality in ≤ 2 years. The mortality showed a positive association with low TC and a negative association with high TC and high LDL-c. After the exclusion of underweight and premature mortality, there was a positive association only with TC <170 mg/dl (HR = 1.36, CI95%: 1.02-1.82). The data did not show a higher risk with high levels of TC, LDL-c, and TG. However, they showed higher mortality among older adults with low TC.


A role for the distal carboxyl tails in generating the novel pharmacology and G protein activation profile of mu and delta opioid receptor hetero-oligomers.
Opioid receptor pharmacology in vivo has predicted a greater number of receptor subtypes than explained by the profiles of the three cloned opioid receptors, and the functional dependence of the receptors on each other shown in gene-deleted animal models remains unexplained. One mechanism for such findings is the generation of novel signaling complexes by receptor hetero-oligomerization, which we previously showed results in significantly different pharmacology for mu and delta receptor hetero-oligomers compared with the individual receptors. In the present study, we show that deltorphin-II is a fully functional agonist of the mu-delta heteromer, which induced desensitization and inhibited adenylyl cyclase through a pertussis toxin-insensitive G protein. Activation of the mu-delta receptor heteromer resulted in preferential activation of Galpha(z), illustrated by incorporation of GTPgamma(35)S, whereas activation of the individually expressed mu and delta receptors preferentially activated Galpha(i). The unique pharmacology of the mu-delta heteromer was dependent on the reciprocal involvement of the distal carboxyl tails of both receptors, so that truncation of the distal mu receptor carboxyl tail modified the delta-selective ligand-binding pocket, and truncation of the delta receptor distal carboxyl tail modified the mu-selective binding pocket. The distal carboxyl tails of both receptors also had a significant role in receptor interaction, as evidenced by the reduced ability to co-immunoprecipitate when the carboxyl tails were truncated. The interaction between mu and delta receptors occurred constitutively when the receptors were co-expressed, but did not occur when receptor expression was temporally separated, indicating that the hetero-oligomers were generated by a co-translational mechanism.


Function of cytokines within the TGF-beta superfamily as determined from transgenic and gene knockout studies in mice.
Several major conceptual problems regarding specific in vivo functions of the TGF-beta family members remain the key focus of many researchers studying the biology of these secreted signaling molecules. More than 45 members of this family of growth factors have been identified and partially characterized for their molecular roles in numerous processes such as cell proliferation and differentiation, embryonic development, carcinogenesis, immune dysfunction, inflammation and wound healing. The high degree of similarity that exists at the structural level among the isoforms of these growth factors is accompanied by a significant overlap in function, as defined by many in vitro model systems and in vivo systems involving administration of exogenous ligand or of ligand-specific blocking antibodies. The ability to discern the critical functions of these molecules based on patterns of expression has also often been quite difficult. The evolution of more sophisticated functional genomics approaches has been recently instrumental in generating unique perspectives into the mechanisms governing the activity of the members of the TGF-beta family. The studies outlined in this review are significant in that they not only support working hypotheses regarding the activities of TGF-beta generated through extensive in vitro studies but also raise new questions regarding the role of each isoform in numerous processes. With the rapid advances in these approaches to probe activity in a more cell and time-dependent fashion, we will gain valuable insights for designing approaches for targeting the complex cellular pathways mediating their responses and will also help us develop novel therapies to treat disease processes.


microRNAs and the mammary gland: A new understanding of gene expression.
MicroRNAs (miRNAs) have been identified in cells as well as in exosomes in biological fluids such as milk. In mammary gland, most of the miRNAs studied have functions related to immunity and show alterations in their pattern of expression during lactation. In mastitis, the inflammatory response caused by Streptococcus uberis alters the expression of miRNAs that may regulate the innate immune system. These small RNAs are stable at room temperature and are resistant to repeated freeze/thaw cycles, acidic conditions and degradation by RNAse, making them resistant to industrial procedures. These properties mean that miRNAs could have multiple applications in veterinary medicine and biotechnology. Indeed, lactoglobulin-free milk has been produced in transgenic cows expressing specific miRNAs. Although plant and animal miRNAs have undergone independent evolutionary adaptation recent studies have demonstrated a cross-kingdom passage in which rice miRNA was isolated from human serum. This finding raises questions about the possible effect that miRNAs present in foods consumed by humans could have on human gene regulation. Further studies are needed before applying miRNA biotechnology to the milk industry. New discoveries and a greater knowledge of gene expression will lead to a better understanding of the role of miRNAs in physiology, nutrition and evolution.


Factors associated with utilisation of traditional Chinese medicine among Hong Kong Chinese.
The present study explored factors associated with belief in, and utilisation of, traditional Chinese medicine (TCM), as well as factors associated with trust in TCM practitioners (TCMPs) among Hong Kong Chinese individuals. Data were collected using a structured questionnaire. A sample of 300 Hong Kong Chinese aged between 18 and 90 years old were recruited. The study used a number of outcome variables including demographic variables, health status, as measured by the SF-12, attitude towards TCM and Western medicine as measured by the Chinese-Western Medical Beliefs Scale, traditional Chinese values as measured by the Chinese Values Scale and trust in physicians. Findings revealed an association between age, gender and education level, with older age, being female and lower educational attainment all being predictive of TCM utilisation. Utilisation norms was predictive of trust in practitioners, indicating that frequent use of TCM lead to higher levels of trust in TCMP. Chinese values were differentially associated with use of and belief in TCM. Confucian obligation was predictive of belief in TCM and utilisation of TCM, while tolerance and harmony was not associated with belief and use of TCM. Younger respondents tended to score higher in tolerance and harmony, while older respondents scored higher in Confucian obligation, which goes some way to explain these differing trends in Chinese values and associations with TCM as older respondents were much more likely to utilise TCM than their younger counterparts.


Reporting randomized, controlled trials: where quality of reporting may be improved.
Evidence-based medicine relies on reproducible, high-quality reporting in the literature. Previous evaluations, which have assessed 11 basic elements of design and analysis in top impact clinical journals (both nonsurgical and surgical), have demonstrated that the reporting quality is less than perfect, although improving. The current study evaluates the quality of reporting in Diseases of the Colon and Rectum and other clinically related journals to identify specific areas where future improvements may be made. Two independent evaluators assessed all randomized, controlled trials published in Diseases of the Colon and Rectum in the years 1990, 1995, and 2000. Additional assessments for 2000 were performed on all randomized, controlled trials published in Annals of Surgery, Archives of Surgery, and Gastroenterology. The frequency of reporting of 11 explicitly defined, traditionally important, basic elements of design and analysis were determined. These elements included reporting of eligibility criteria, admission before allocation, randomization (and method), blinded assessment (patient and observer), complications, loss to follow-up, statistical approach and tests, and power calculation. Interobserver reliability was strong (kappa, 0.76). The number of randomized, controlled trials published in Diseases of the Colon and Rectum increased from 5 (in 1990) to 13 (in 1995) to 17 (in 2000). Of the 1990 randomized, controlled trials, an average of 60 percent of the 11 basic elements were reported. Of the 1995 randomized, controlled trials, 72 percent of the items were reported (P = 0.05), whereas of the 2000 randomized, controlled trials, 77 percent of the 11 items were reported (P < 0.002 vs. 1990). The best-reported items were eligibility criteria, discussion of statistical tests, and accounting for all patients lost to follow-up. Only 11 percent of the 2000 randomized, controlled trials reported statistical power calculations. For the other journals that were evaluated, 72 to 88 percent of items were reported, with eligibility criterion being the best consistently reported item and power calculation being the worst. For Diseases of the Colon and Rectum, the number of randomized, controlled trials and the quality of reporting is improving. However, although certain research standards are reported adequately, others are not. The calculation of statistical power is clearly important when interpreting randomized, controlled trial results (whether differences are reported or not), yet only 11 percent of studies contained this information. Improving the reporting of this single item would likely lead to improving the overall quality of clinical studies in colorectal surgery. Improved reporting might be best facilitated by having authors adhere to a list of explicitly determined elements that should be included.


Determination of Fragility in Organic Small Molecular Glass Forming Liquids: Comparison of Calorimetric and Spectroscopic Data and Commentary on Pharmaceutical Importance.
The fragility index ( m) and conversely the strength parameter ( D) are widely used to categorize glass forming liquids and are used to characterize temperature dependency of viscosity and relaxation time as the supercooled liquid approaches glass transition. The currently used calorimetric methods in pharmaceutical literature lead to wide variability in measured values of m. In this work, a modulated differential scanning calorimetry (DSC) method is introduced that can directly determine m with minimal variability. Although calorimetric fragility is easy to measure due to availability and ease of use of DSC, there is no correlation between calorimetric and dielectric fragility (calculated spectroscopically from relaxation times). In addition, there is also no correlation between calorimetric fragility and the so-called "thermodynamic fragility" that can be calculated using only thermodynamic parameters. No relationship can be found between the crystallization propensity in the supercooled liquid state and D. However, the crystallization propensity shows a reasonable correlation with the Kohlrausch distribution parameter βk, which defines the breadth of the relaxation time distribution.


Abnormally primed CD8 T cells: The Achilles' heel of CHB.
Chronic hepatitis B virus (HBV) infection continues to be a significant public health challenge, and more than 250 million people around world are infected with HBV. The clearance of HBV with virus-specific CD8 T cells is critical for a functional cure. However, naïve HBV-specific CD8 T cells are heavily hindered during the priming process, and this phenomenon is closely related to abnormal cell and signal interactions in the complex immune microenvironment. Here, we briefly summarize the recent progress in understanding the abnormal priming of HBV-specific CD8 T cells and some corresponding immunotherapies to facilitate their functional recovery, which provides a novel perspective for the design and development of immunotherapy for chronic HBV infection (CHB). Finally, we also highlight the balance between viral clearance and pathological liver injury induced by CD8 T-cell activation that should be carefully considered during drug development.


High energy flux mediates the tonically augmented beta-adrenergic support of resting metabolic rate in habitually exercising older adults.
The sympathetic nervous system contributes to resting metabolic rate (RMR) via beta-adrenergic receptor (beta-AR) stimulation of energy metabolism. RMR and beta-AR support of RMR are greater in habitually exercising compared with sedentary older adults possibly due to greater energy flux (magnitude of energy intake and energy expenditure during energy balance). In 10 older adults regularly performing aerobic endurance exercise (mean +/- se, 66 +/- 1 yr) compared with baseline, a reduction in energy flux (via abstention of exercise and proportional reduction in dietary intake) decreased (P < 0.05) energy expenditure (7746 +/- 440 vs. 9630 +/- 662 kJ.d(-1)), caloric intake (7808 +/- 431 vs. 9433 +/- 528 kJ.d(-1)), RMR (5192 +/- 167 vs. 5401 +/- 209 kJ.d(-1)), and skeletal muscle sympathetic nervous system activity (36 +/- 2 vs. 42 +/- 2 bursts.min(-1)). Significant beta-AR support of RMR was observed at baseline (167 +/- 42 kJ.d(-1)) but not during reduced energy flux. The change in RMR from baseline to reduced energy flux was related to the corresponding change in beta-AR support of RMR (r = 0.77, P = 0.009). No changes were observed in seven time controls (69 +/- 3 yr) who maintained energy flux. High energy flux is a key mechanism contributing to the elevated RMR and beta-AR support of RMR in habitually exercising older adults. Maintenance of high energy flux via regular exercise may be an effective strategy for maintaining energy expenditure and preventing age-associated obesity.


Next-generation Sequencing of the DNA Virome from Fecal Samples.
Herein we describe a detailed protocol for DNA virome analysis of low input human stool samples (Monaco et al., 2016). This protocol is divided into four main steps: 1) stool samples are pulverized to evenly distribute microbial matter; 2) stool is enriched for virus-like particles and DNA is extracted by phenol-chloroform; 3) purified DNA is multiple-strand displacement amplified (MDA) and fragmented; and 4) libraries are constructed and sequenced using Illumina Miseq. Subsequent sequence analysis for viral sequence identification should be sensitive but stringent.


Functional platelet defects in children with severe chronic ITP as tested with 2 novel assays applicable for low platelet counts.
Immune thrombocytopenia (ITP) is an autoimmune disease with a complex heterogeneous pathogenesis and a bleeding phenotype that is not necessarily correlated to platelet count. In this study, the platelet function was assessed in a well-defined cohort of 33 pediatric chronic ITP patients. Because regular platelet function test cannot be performed in patients with low platelet counts, 2 new assays were developed to determine platelet function: first, the microaggregation test, measuring in platelets isolated from 10 mL of whole blood the platelet potential to form microaggregates in response to an agonist; second, the platelet reactivity assay, measuring platelet reactivity to adenosine diphosphate (ADP), convulxin (CVX), and thrombin receptor activator peptide in only 150 μL of unprocessed whole blood. Patients with a severe bleeding phenotype demonstrated a decreased aggregation potential upon phorbol myristate acetate stimulation, decreased platelet degranulation following ADP stimulation, and a higher concentration of ADP and CVX needed to activate the glycoprotein IIbIIIa complex compared with patients with a mild bleeding phenotype. In conclusion, here we have established 2 functional tests that allow for evaluation of platelet function in patients with extremely low platelet counts (<10(9)). These tests show that platelet function is related to bleeding phenotype in chronic ITP.


Supporting preceptors.
For effective teaching of nursing students and management of stress of increased workloads, preceptors require a great deal of support from nursing faculty, peers, and administrative personnel. Through a mailed survey, 295 preceptors reported that they would have appreciated more support. The best support is the continued and visible presence and involvement of instructors, which can be provided in person, by telephone, or via fax. This is best achieved if nurse educators, directors, and deans view themselves as copreceptors.


Development and validation of the type 1 diabetes nutrition knowledge survey.
The purpose of this study was to develop a survey of general and diabetes-specific nutrition knowledge for youth with type 1 diabetes and their parents and to assess the survey's psychometric properties. A multidisciplinary pediatric team developed the Nutrition Knowledge Survey (NKS) and administered it to youth with type 1 diabetes (n = 282, 49% females, 13.3 ± 2.9 years) and their parents (82% mothers). The NKS content domains included healthful eating, carbohydrate counting, blood glucose response to foods, and nutrition label reading. Higher NKS scores reflect greater nutrition knowledge (score range is 0-100%). In youths, glycemic control was assessed by A1C, and dietary quality was determined by the Healthy Eating Index-2005 (HEI-2005) derived from 3-day diet records. Validity was based on associations of NKS scores with A1C and dietary quality. Reliability was assessed using the Kuder-Richardson Formula 20 (KR-20) and correlations of domain scores to total score. Mean NKS scores (23 items) were 56.9 ± 16.4% for youth and 73.4 ± 12.5% for parents. The KR-20 was 0.70 for youth and 0.59 for parents, representing acceptable internal consistency of the measure. In multivariate analysis, controlling for youth age, family income, parent education, diabetes duration, and insulin regimen, parent NKS scores were associated with corresponding youth A1C (β = -0.13, P = 0.03). Both parent (β = 0.20, P = 0.002) and youth (β = 0.25, P < 0.001) NKS scores were positively associated with youth HEI-2005 scores. The NKS appears to be a useful measure of general and diabetes-specific nutrition knowledge for youth with type 1 diabetes and their parents.


[Typical from and basic variants of the structure of the intrahepatic portion of the portal vein].
The structure of the portal vein was studied in 210 preparations of the liver. The structure of the main trunk of the portal vein and its lobe branches was estimated orienting by the typical shape and the main variations of the structure. Two variants of the structure of the right and left portal veins (after the type of a "pine branch" and the variant of the "minimum length" of the lobe vein) were common for both veins. The structure of the "snail" type was found only in the left portal vein of the "whisk" type -- only in the right one. The sources of the segment blood supply changed depending on the structure of the main trunk and lobe veins. They can be supplied by terminal or lateral branches of the lobe veins, vascular branches of the main trunk of the portal vein and of the vessels of neighbouring segments. Estimation of the angioarchitectonics of the liver operated on should be approached individually in each case. It is expedient to take into account the above typical shape and the main variants of the intrahepatic portion of the portal vein.


The Developmental Profile: its use in establishing indications for psychoanalytic treatment.
The Developmental Profile offers a description of the degree to which an adult has developed adaptive behavioral functions appropriate to his or her age and the extent to which his or her functioning is determined by "early," now maladaptive, patterns. After examining the structure, the application, and the psychometric evaluation of the Developmental Profile, the authors describe how this profile can be used to support the process of selecting a psychoanalytic treatment.


5-Bromo-4',5'-bis(dimethylamino)fluorescein: Synthesis and Photophysical Studies.
In this study, three new fluorescein derivatives-5-bromo-4',5'-dinitrofluorescein (BDNF), 5-bromo-4',5'-diaminofluorescein (BDAF), and 5-bromo-4',5'-bis(dimethylamino)fluorescein (BBDMAF)-were synthesized and their pH-dependent protolytic equilibria were investigated. In particular, BBDMAF exhibited pH-dependent fluorescence, showing strong emission only at pH 3-6. BBDMAF bears a bromine moiety and thus, can be used in various cross-coupling reactions to prepare derivatives and take advantage of its unique emission properties. To confirm this, the Suzuki and Sonogashira reactions of BBDMAF with phenylboronic acid and phenylacetylene, respectively, were performed, and the desired products were successfully obtained.


The cardiovascular effects of adenosine: clinical use and nursing implications.
Adenosine, an endogenous nucleoside, is involved in numerous biologic processes. An important regulator of cardiac rhythm and coronary blood flow, adenosine is useful in the diagnosis and treatment of PSVT. In addition, adenosine may soon be available for cardiac imaging and eventually as a protective agent against acute myocardial infarction and reperfusion injury. This article reviews the cardiovascular effects of adenosine, its diagnostic and therapeutic utility, and the implications for nursing care.


Effects of a novel immunosuppressive agent, FK506, on human B cell activation.
We examined the effect of new immunosuppressive agent, FK506, on the human B cell function, in comparison with that of cyclosporin A (CyA) and tried to define the discrete activation step(s) which is selectively affected by FK506 and CyA. We used polyclonal B cell activators, Staphylococcus aureus Cowan I (SAC) and pokeweed mitogen (PWM). We found that (i) the initial B cell activation process by PWM, which is on the basis of T cell-dependent manner, is susceptible to the inhibitory effects of FK506 and CyA, while initial B cell activation on the basis of T cell-independent manner by SAC is resistant to these drugs; (ii) they also inhibit helper factor production by T cells; (iii) once they are activated, the B cells become resistant to inhibition by the drugs; and (iv) on an equimolar basis, FK506 exhibits 100-fold greater inhibitory activity than does CyA. Thus FK506 mainly interferes with interactions between T cells and other cells which are essential for B cell activation process, resulting in inhibition of B cell function.


Suzuki-type cross-coupling of alkyl trifluoroborates with acid fluoride enabled by NHC/photoredox dual catalysis.
The Suzuki-Miyaura cross-coupling of C(sp3)-hybridised boronic compounds still remains a challenging task, thereby hindering the broad application of alkyl boron substrates in carbon-carbon bond-forming reactions. Herein, we developed an NHC/photoredox dual catalytic cross-coupling of alkyl trifluoroborates with acid fluorides, providing an alternative solution to the classical acylative Suzuki coupling chemistry. With this protocol, various ketones could be rapidly synthesised from readily available materials under mild conditions. Preliminary mechanistic studies shed light on the unique radical reaction mechanism.


Studies of male reproduction in captive African wild dogs (Lycaon pictus).
Implementation of assisted breeding in the captive African wild dog is restricted by a current lack of knowledge on their reproductive physiology and the apparent difficulty of effectively manipulating the complex social dynamic of the pack in order to conduct reproductive procedures. In this study, we describe protocols for the safe and repeated capture and restraint of the African wild dog (n=7) as well as techniques for assessment of male reproductive function, semen collection and preservation. In a serendipitous finding, captive African wild dogs appeared to display significant seasonal change in male reproduction. Testicular volume and tone, spermatorrhea and the ability to collect semen by electroejaculation all increased significantly during late summer and then subsequently declined by early spring. While there were no detectable seasonal changes in testosterone concentration in the population as whole, the alpha-dominant male in both years of the study, had a highly elevated testosterone concentration compared to subordinate males. Semen collection by electroejaculation during the late summer was most effective in peri-pubertal males (15 months) when all seven electroejaculates were of adequate quality for cryopreservation. In the second breeding season (27 months), there were numerous changes in the pack hierarchy and electroejaculation was not as successful (3/7). The characteristics of electroejaculated semen collected in the breeding season are described for seven animals including the first descriptions and incidence of sperm abnormalities in the species. Semen (n=7) was frozen using a Tris-citrate fructose buffer and final egg yolk and glycerol concentration of 20% and 4%, respectively. Sperm were loaded into 0.25 mL straws, frozen in liquid nitrogen vapor and then thawed at 37 degrees C. Initial post-thaw survival of spermatozoa was encouraging (% motile: 31.8+/-5.8%; rate: 2.8+/-0.3; % intact plasma membranes: 33.4+/-5.3% and the % of damaged acrosomes: 4.4+/-1.5%) but following 2 h incubation at 37 degrees C, post-thaw survival declined markedly.


L-656,575 (OCP-9-176): a novel oxacephem. Pharmacokinetics and experimental chemotherapy.
L-656,575 is a new oxacephem that, based on studies in rhesus monkeys, is expected to have a moderately long half-life in humans. After administration of a 10-mg/kg dose by the intramuscular route to rhesus monkeys, peak serum concentrations of 32-54 micrograms/ml were seen at about 30 minutes, and the half-life was estimated to be 63 minutes. Urinary recovery of administered dose was greater than 94% in 6 hours. In mice given a 20-mg/kg dose by the subcutaneous route, a peak serum concentration of 22.9 microgram/ml was observed at 15 minutes after dosing, and the half-life in serum was about 18 minutes. Urinary recovery of the dose was 59% in 6 hours. In another study in mice, administration of probenecid did not extend the half-life of L-656,575, suggesting that the antibiotic is excreted primarily by glomerular filtration in this species. Binding to human plasma proteins was 30% at drug concentrations from 25-100 micrograms/ml. L-656,575 also was shown to be efficacious in experimental bacteremias due to Gram-positive and Gram-negative pathogens in mice, thus confirming the broad spectrum of activity demonstrated for L-656,575 in vitro.


Impaired insulin-receptor autophosphorylation is an early defect in fat-fed, insulin-resistant rats.
High-fat feeding results in impaired insulin signaling in skeletal muscle, but the role of the insulin receptor (IR) remains controversial. In the present study, female Fischer 344 rats were fed diets either low in fat [low fat, complex carbohydrate (LFCC)] or high in fat and sucrose (HFS). Insulin-stimulated skeletal muscle glucose transport, measured in purified sarcolemmal vesicles, was lower in rats consuming the HFS diet for 2 and 8 wk compared with LFCC controls (72.9 +/- 3.5, 67.6 +/- 3.5, and 86.1 +/- 3.5 pmol x mg(-1) x 15 s(-1), respectively; P < 0.05). Muscle IR content was unchanged in 2-wk HFS animals but was 50% lower in the 8-wk HFS group (P < 0.001). However, compared with LFCC, insulin-stimulated IR autophosphorylation was 26% lower in 2-wk HFS and 40% lower in 8-wk HFS animals (P < 0.005). Total muscle content of the proposed IR inhibitors cytokine tumor necrosis factor-alpha and membrane glycoprotein PC-1 was not significantly changed in HFS animals at either 2 or 8 wk. These results demonstrate that high-fat feeding induces insulin resistance in muscle concomitant with a diminished IR signaling capacity, although the mechanism remains unknown.


Strain of bone-implant interface and insertion torque regarding different miniscrew thread designs using an artificial bone model.
To evaluate the initial stability of dual-thread miniscrews by analyzing the strain at the bone-implant interface and insertion torque during implantation in artificial bone models with different cortical bone thicknesses. Insertion torque, and strain, measured with a five-element strain gauge in 1.0, 1.5, and 2.0-mm artificial cortical bone, during insertion of single- (OAS-T1507) and dual-thread (MPlant-U3) type self-drilling miniscrews were assessed. Both dual- and single-thread miniscrews showed greater than 7790 μstrain for all cortical bone thicknesses, and dual-thread miniscrews reached up to 19580 μstrain in 2.00 m m cortical bone. The strain of dual-thread miniscrews increased with increasing cortical bone thicknesses of 1.0-2.0mm. For single-thread miniscrews, the maximum insertion torque was relatively constant, but maximum insertion torque increased significantly in dual-thread groups with increasing cortical bone thicknesses (P < 0.0001). The maximum insertion torque with all cortical bone thicknesses was significantly lower with single- than dual-thread types (P < 0.0001). Self-drilling dual-thread miniscrews provide better initial mechanical stability, but may cause strain over the physiological bone remodelling limit at the bone-implant interface in thick cortical bone layers.


Tree lizard (Urosaurus ornatus) growth decreases with population density, but increases with habitat quality.
Habitat selection models can explain spatial patterns in the relative abundance of animals in different habitats based on the assumption that fitness declines as density in a habitat increases. Ectotherms, such as lizards, may not follow predictions of density-dependent habitat selection models because temperature, which is unaffected by density, strongly influences their habitat selection. If competition for limited resources decreases fitness, then crowding should cause a decrease in body size and growth rates. We used skeletochronology and body size data from tree lizards (Urosaurus ornatus) at six sites that each spanned two habitats varying in quality to test the hypothesis that habitat selection is density dependent because growth is limited by competition for resources and by habitat quality. First, we tested that the maximum body size of lizards decreased with higher densities in a habitat by comparing growth between sites. Second, we tested whether body size and growth were higher in the habitat with more resources by controlling for density in a habitat and comparing growth between habitats in different sites. We found evidence of density-dependent growth in females, but not in males. Females in more crowded sites reached a smaller maximum size. Females in the higher quality habitat also grew larger than females in the lower quality habitat after controlling for differences in density between the habitats. Therefore, we found partial support for our hypothesis that competition for resources limits growth and causes density-dependent habitat selection.


Risk of graft fracture after dorso-ventral thoraco-lumbar spondylodesis: is there a correlation with graft size?
Retrospective clinical study in patients with dorso-ventral thoraco-lumbar spondylodesis. To investigate whether the ratio between graft cross sectional area and the surface area of the adjacent endplates has any effect on the midterm stability of the spondylodesis. Dorso-ventral spondylodesis in the region of the thoraco-lumbar spine is one of the most frequent operations in orthopaedic surgery. Anterior stabilization with autologous iliac crest graft currently is a standard approach in many hospitals. Although numerous recommendations are given how to perform this technique, no clinical advice is available with regard to minimum graft size. Sixty-four-slice CT-scans were obtained from 82 patients 4-12 months after posterior spondylodesis with anterior implantation of iliac crest graft and stabilization with an internal fixator. The scans were analyzed using image analysis software. First, the cross sectional area of the graft was calculated and then the surface area of the adjacent endplates. The ratio between graft cross sectional area and endplate surface area was then calculated from these two values. The grafts were then evaluated in sagittal reconstruction for signs of fracture. The probability for graft fracture in autologous tricortical grafts was >0.1% (p < 0.001) if the graft cross sectional area exceeded 23.9% of the surface area of the adjacent endplates. Patients with lower ratio values had a higher fracture risk and below a value of 10% all grafts fractured. The relationship between graft cross sectional area and adjacent endplate area has an important effect on graft midterm stability in ventral spondylodesis of the thoraco-lumbar spine. In our opinion, the risk of graft fractures in dorso-ventral spondylodesis can be reduced by implantation of an appropriately sized graft without any additional procedures or instrumentation.


Incidental detection of carcinoma of the prostate while staging carcinoma of the rectum with transrectal ultrasound.
This case report describes the unanticipated results of a transrectal ultrasound performed to stage a cancer of the rectum. During sonography, the normally dense prostate peripheral zone produced weak echoes indicating the existence of an unexpected carcinoma of the prostate. The presence of extensive prostate cancer was subsequently verified by biopsy.


Association of sick sinus and Lown-Ganong-Levine syndromes.
A 38-year-old woman presented with syncopal attacks for 27 years. The electrophysiology techniques which enabled the diagnosis of both sinus node dysfunction (sick sinus syndrome) and presence of an atrionodal bypass tract (Lown-Ganong-Levine syndrome) are illustrated.


[Differential diagnosis of thyrotoxicosis in subjects with post-immunization reaction].
An increasingly greater fraction of the general population is getting involved in the immunization program. However, conditions of individual subjects are not always properly evaluated prior to immunization. The clinical case reported below demonstrates the difficulty of diagnostic examination of patients with Graves disease (toxic goiter), endocrine ophthalmopathy, and post-immunization reaction.


Phase III trials of targeted anticancer therapies: redesigning the concept.
Randomized phase III trials provide the gold-standard evidence for the approval of new drugs: an experimental treatment is compared with the current standard of care to identify clinically relevant differences in a predefined endpoint. However, there are several problems relating to the current role of phase III trials in drug development including the limited clinical benefit observed for some approved agents, the necessity for large trials to detect these differences, the inability of such trials to identify rare but important toxicities, and high cost. The design of phase III trials evaluating drug combinations, and those including biomarkers, presents additional challenges. Here, we review these problems and suggest that phase III trials with adaptive designs in selected prescreened populations could reduce these limitations.


Statistical Framework in Support of a Revised Children's Oncology Group Neuroblastoma Risk Classification System.
The International Neuroblastoma Risk Group (INRG) Staging System (INRGSS) was developed through international consensus to provide a presurgical staging system that uses clinical and imaging data at diagnosis. A revised Children's Oncology Group (COG) neuroblastoma (NB) risk classification system is needed to incorporate the INRGSS and within the context of modern therapy. Herein, we provide statistical support for the clinical validity of a revised COG risk classification system. Nine factors were tested for potential statistical and clinical significance in 4,569 patients diagnosed with NB who were enrolled in the COG biology/banking study ANBL00B1 (2006-2016). Recursive partitioning was performed to create a survival-tree regression (STR) analysis of event-free survival (EFS), generating a split by selecting the strongest prognostic factor among those that were statistically significant. The least absolute shrinkage and selection operator (LASSO) was applied to obtain the most parsimonious model for EFS. COG patients were risk classified using STR, LASSO, and per the 2009 INRG classification (generated using an STR analysis of INRG data). Results were descriptively compared among the three classification approaches. The 3-year EFS and overall survival (± SE) were 72.9% ± 0.9% and 84.5% ± 0.7%, respectively (N = 4,569). In each approach, the most statistically and clinically significant factors were diagnostic category (eg, NB, ganglioneuroblastoma), INRGSS, MYCN status, International Neuroblastoma Pathology Classification, ploidy, and 1p/11q status. The results of the STR analysis were more concordant with those of the INRG classification system than with LASSO, although both methods showed moderate agreement with the INRG system. These analyses provide a framework to develop a new COG risk classification incorporating the INRGSS. There is statistical evidence to support the clinical validity of each of the three classifications: STR, LASSO, and INRG.


Polarized tip-enhanced Raman spectroscopy at liquid He temperature in ultrahigh vacuum using an off-axis parabolic mirror.
Tip-enhanced Raman spectroscopy (TERS) combines inelastic light scattering well below the diffraction limit down to the nanometer range and scanning probe microscopy and, possibly, spectroscopy. In this way, topographic and spectroscopic as well as single- and two-particle information may simultaneously be collected. While single molecules can now be studied successfully, bulk solids are still not meaningfully accessible. It is the purpose of the work presented here to outline approaches toward this objective. We describe a home-built, liquid helium cooled, ultrahigh vacuum TERS. The setup is based on a scanning tunneling microscope and, as an innovation, an off-axis parabolic mirror having a high numerical aperture of ∼0.85 and a large working distance. The system is equipped with a fast load-lock chamber, a chamber for the in situ preparation of tips, substrates, and samples, and a TERS chamber. Base pressure and temperature in the TERS chamber were ∼3 × 10-11 mbar and 15 K, respectively. Polarization dependent tip-enhanced Raman spectra of the vibration modes of carbon nanotubes were successfully acquired at cryogenic temperature. The new features described here including very low pressure and temperature and the external access to the light polarizations, thus the selection rules, may pave the way toward the investigation of bulk and surface materials.


[Neural correlates of priming in vision: evidence from neuropsychology and neuroimaging].
When we look around us, we are overall more likely to notice objects that we have recently looked at; an effect known as priming. For example, when the color or shape of a visual search target is repeated, observers find the target faster than otherwise. Here I summarize recent research undertaken to uncover the temporary changes in brain activity that accompany these priming effects. In light of the fact that priming seems to have a large effect on how attention is allocated, we investigated priming effects in a visual search task on patients suffering from the neurological disorder "hemispatial neglect" in which patients typically fail to notice display items in one of their visual hemifields. Priming of target color was relatively normal for these patients, while priming of target location seemed to require awareness of the briefly presented visual search target. An experiment with functional magnetic resonance imaging of normal observers revealed that both color and location priming had a strong modulatory influence on attentional mechanisms of the frontal and parietal cortex. Color priming was also correlated with changes in activity in visual cortex as well as color processing areas in the temporal lobe. Location priming was correlated with changes in activity near the temporo- parietal junction and lateral inferior frontal cortex, areas that have been connected with attentional capture; which ties well with our finding of deficits of location priming for the neglect patients who indeed have lesions in the temporo-parietal junction. Overall, the results confirm the tight coupling of visual attention and priming in vision, and also that the visual areas of the brain show some modulation of activity as priming develops.


Induction of thioredoxin reductase gene expression by peroxynitrite in human umbilical vein endothelial cells.
Thioredoxin reductase (TR), a flavoprotein, catalyzes the reduction of oxidized thioredoxin in a NADPH-dependent manner, and contains a selenocysteine residue near the C-terminus. TR plays an important role in protecting against oxidative stress and in regulating cell growth and cell death. Constitutive TR expression has been observed in several cell types of the mammalian body, including endothelial cells. The latter are continually exposed to both exogenous and endogenous sources of nitric oxide (NO) and NO-derived species. Reactive nitrogen species (RNS) are associated with pathological events, contributing to the cell and tissue damage accompanying inflammation, atherogenesis and autoimmune diseases. In this study, we report on the effect of peroxynitrite on TR in human umbilical vein endothelial cells (HUVECs). Exposure to the peroxynitrite donor SIN-1 for 1 h resulted in a decrease in TR activity. Interestingly, the activity was completely restored within 24 h. To further examine this mechanism, the expression of TR at the mRNA and protein level was examined. TR mRNA levels were markedly increased by treatment of SIN-1 within 6 h, and TR protein level was also increased after the treatment in HUVECs. These results suggest that the inactivation of TR by peroxynitrite might be involved in the upregulation of the TR gene in HUVECs. Therefore, HUVECs have a unique protective mechanism that allows the maintenance of balance in intracellular redox status via TR induction as an adaptive response to nitrooxidative stress.


Changes in the number of double-strand DNA breaks in Chinese hamster V79 cells exposed to γ-radiation with different dose rates.
A comparative investigation of the induction of double-strand DNA breaks (DSBs) in the Chinese hamster V79 cells by γ-radiation at dose rates of 1, 10 and 400 mGy/min (doses ranged from 0.36 to 4.32 Gy) was performed. The acute radiation exposure at a dose rate of 400 mGy/min resulted in the linear dose-dependent increase of the γ-H2AX foci formation. The dose-response curve for the acute exposure was well described by a linear function y = 1.22 + 19.7x, where "y" is an average number of γ-H2AX foci per a cell and "x" is the absorbed dose (Gy). The dose rate reduction down to 10 mGy/min lead to a decreased number of γ-H2AX foci, as well as to a change of the dose-response relationship. Thus, the foci number up to 1.44 Gy increased and reached the "plateau" area between 1.44 and 4.32 Gy. There was only a slight increase of the γ-H2AX foci number (up to 7) in cells after the protracted exposure (up to 72 h) to ionizing radiation at a dose rate of 1 mGy/min. Similar effects of the varying dose rates were obtained when DNA damage was assessed using the comet assay. In general, our results show that the reduction of the radiation dose rate resulted in a significant decrease of DSBs per cell per an absorbed dose.


Primary umbilical endometriosis: case report and literature review.
We present a case of primary endometriosis of the umbilicus in a young nulliparous patient without any previous history of abdominal or pelvic surgery. Primary endometriosis of extra pelvic sites is unusual while umbilical endometriosis is quite rare. Diagnosis of endometriosis is difficult to obtain and sometimes diagnoses can be false-positive or false-negative. Some imaging procedures can be done to rule out other disorders but it is difficult to differentiate them from endometriosis. A definite diagnosis can only be established by histopathological examination. Hematoxylin and eosin (H&E) is the staining of choice. Conservative surgical excision of the lesion and drugs such as oral contraceptives and gonadotropin releasing analogues are the first-line treatment.


Multimodality imaging of Alzheimer disease and other neurodegenerative dementias.
Neurodegenerative diseases, such as Alzheimer disease, result in cognitive decline and dementia and are a leading cause of mortality in the growing elderly population. These progressive diseases typically have an insidious onset, with overlapping clinical features early in the disease course that make diagnosis challenging. The neurodegenerative diseases are associated with characteristic, although not completely understood, changes in the brain: abnormal protein deposition, synaptic dysfunction, neuronal injury, and neuronal death. Neuroimaging biomarkers-principally regional atrophy on structural MR imaging, patterns of hypometabolism on (18)F-FDG PET, and detection of cerebral amyloid plaque on amyloid PET--are able to evaluate the patterns of these abnormalities in the brain to improve early diagnosis and help predict the disease course. These techniques have unique strengths and synergies in multimodality evaluation of the patient with cognitive decline or dementia. This review discusses the key imaging biomarkers from MR imaging, (18)F-FDG PET, and amyloid PET; the imaging features of the most common neurodegenerative dementias; the role of various neuroimaging studies in differential diagnosis and prognosis; and some promising imaging techniques under development.


Non-pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome.
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder in which the two main clinical features are pelvic pain and lower urinary tract symptoms. There are currently many approaches for its management, using both pharmacological and non-pharmacological interventions. The National Institute of Health - Chronic Prostatitis Symptom Index (NIH-CPSI) score is a validated measure commonly used to measure CP/CPPS symptoms. To assess the effects of non-pharmacological therapies for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). We performed a comprehensive search using multiple databases, trial registries, grey literature and conference proceedings with no restrictions on the language of publication or publication status. The date of the latest search of all databases was August 2017. We included randomised controlled trials. Inclusion criteria were men with a diagnosis of CP/CPPS. We included all available non-pharmacological interventions. Two review authors independently classified studies and abstracted data from the included studies, performed statistical analyses and rated quality of evidence (QoE) according to the GRADE methods. We included 38 unique studies with 3290 men with CP/CPPS across 23 comparisons.1. Acupuncture: (three studies, 204 participants) based on short-term follow-up, acupuncture reduces prostatitis symptoms in an appreciable number of participants compared with sham procedure (mean difference (MD) in total NIH-CPSI score -5.79, 95% confidence interval (CI) -7.32 to -4.26, high QoE). Acupuncture likely results in little to no difference in adverse events (moderate QoE). It probably also decreases prostatitis symptoms compared with standard medical therapy in an appreciable number of participants (MD -6.05, 95% CI -7.87 to -4.24, two studies, 78 participants, moderate QoE).2. Circumcision: (one study, 713 participants) based on short-term follow-up, early circumcision probably decreases prostatitis symptoms slightly (NIH-CPSI score MD -3.00, 95% CI -3.82 to -2.18, moderate QoE) and may not be associated with a greater incidence of adverse events compared with control (a waiting list to be circumcised, low QoE).3. Electromagnetic chair: (two studies, 57 participants) based on short-term follow-up, we are uncertain of the effects of the use of an electromagnetic chair on prostatitis symptoms. It may be associated with a greater incidence of adverse events compared with sham procedure (low to very low QoE).4. Lifestyle modifications: (one study, 100 participants) based on short-term follow-up, lifestyle modifications may be associated with a greater improvement in prostatitis symptoms in an appreciable number of participants compared with control (risk ratio (RR) for improvement in NIH-CPSI scores 3.90, 95% CI 2.20 to 6.92, very low QoE). We found no information regarding adverse events.5. Physical activity: (one study, 85 participants) based on short-term follow-up, a physical activity programme may cause a small reduction in prostatitis symptoms compared with control (NIH-CPSI score MD -2.50, 95% CI -4.69 to -0.31, low QoE). We found no information regarding adverse events.6. Prostatic massage: (two studies, 115 participants) based on short-term follow-up, we are uncertain whether the prostatic massage reduces or increases prostatitis symptoms compared with control (very low QoE). We found no information regarding adverse events.7. Extracorporeal shockwave therapy: (three studies, 157 participants) based on short-term follow-up, extracorporeal shockwave therapy reduces prostatitis symptoms compared with control (NIH-CPSI score MD -6.18, 95% CI -7.46 to -4.89, high QoE). These results may not be sustained at medium-term follow-up (low QoE). This treatment may not be associated with a greater incidence of adverse events (low QoE).8. Transrectal thermotherapy compared to medical therapy: (two studies, 237 participants) based on short-term follow-up, transrectal thermotherapy alone or in combination with medical therapy may decrease prostatitis symptoms slightly when compared with medical therapy alone (NIH-CPSI score MD -2.50, 95% CI -3.82 to -1.18, low QoE). One included study reported that participants may experience transient adverse events.9. Other interventions: there is uncertainty about the effects of other interventions included in this review. We found no information regarding psychological support or prostatic surgery. Some of the interventions can decrease prostatitis symptoms in an appreciable number without a greater incidence of adverse events. The QoE was mostly low. Future clinical trials should include a full report of their methods including adequate masking, consistent assessment of all patient-important outcomes including potential treatment-related adverse events and appropriate sample sizes.


The Creative Benefits Scale: Connecting Generativity to Life Satisfaction.
Long-term participation in creative activities has benefits for middle-aged and older people that may improve their adaptation to later life. We first investigated the factor structure of the Creative Benefits Scale and then used it to construct a model to help explain the connection between generativity and life satisfaction in adults who participated in creative hobbies. Participants included 546 adults between the ages of 40 and 88 (Mean = 58.30 years) who completed measures of life satisfaction, generativity, and the Creative Benefits Scale with its factors of Identity, Calming, Spirituality, and Recognition. Structural equation modeling was used to examine the connection of age with life satisfaction in older adults and to explore the effects of creativity on this relation. The proposed model of life satisfaction, incorporating age, creativity, and generativity, fit the data well, indicating that creativity may help explain the link between the generativity and life satisfaction.


Recent ecological responses to climate change support predictions of high extinction risk.
Predicted effects of climate change include high extinction risk for many species, but confidence in these predictions is undermined by a perceived lack of empirical support. Many studies have now documented ecological responses to recent climate change, providing the opportunity to test whether the magnitude and nature of recent responses match predictions. Here, we perform a global and multitaxon metaanalysis to show that empirical evidence for the realized effects of climate change supports predictions of future extinction risk. We use International Union for Conservation of Nature (IUCN) Red List criteria as a common scale to estimate extinction risks from a wide range of climate impacts, ecological responses, and methods of analysis, and we compare predictions with observations. Mean extinction probability across studies making predictions of the future effects of climate change was 7% by 2100 compared with 15% based on observed responses. After taking account of possible bias in the type of climate change impact analyzed and the parts of the world and taxa studied, there was less discrepancy between the two approaches: predictions suggested a mean extinction probability of 10% across taxa and regions, whereas empirical evidence gave a mean probability of 14%. As well as mean overall extinction probability, observations also supported predictions in terms of variability in extinction risk and the relative risk associated with broad taxonomic groups and geographic regions. These results suggest that predictions are robust to methodological assumptions and provide strong empirical support for the assertion that anthropogenic climate change is now a major threat to global biodiversity.