Parallel dose-response curves in combination experiments.
A possible experimental design for combination experiments is to compare the dose-response curve of a single agent with the corresponding curve of the same agent using either a fixed amount of a second one or a fixed dose ratio. No interaction is then often defined by a parallel shift of these curves. We have performed a systematic study for various types of dose-response relations both for the dose-additivity (Loewe additivity) and for the independence (Bliss independence) criteria for defining zero interaction. Parallelism between dose-response curves of a single agent and those of the same agent in the presence of a fixed amount of another one is found for the Loewe-additivity criterion for linear dose-response relations. For nonlinear relations, one has to differentiate between effect parallelism (parallel shift on the effect scale) and dose parallelism (parallel shift on the dose scale). In the case of Loewe additivity, zero-interaction dose parallelism is found for power, Weibull, median-effect and logistic dose-response relations, given that special parameter relationships are fulfilled. The mechanistic model of competitive interaction exhibits dose parallelism but not effect parallelism for Loewe additivity. Bliss independence and Loewe additivity lead to identical results for exponential dose-response curves. This is the only case for which dose parallelism was found for Bliss independence. Parallelism between single-agent dose-response relations and Loewe additivity mixture relations is found for examples with a fixed dose-ratio design. However, this is again not a general property of the design adopted but holds only if special conditions are fulfilled. The comparison of combination dose-response curves with single-agent relations has to be performed taking into account both potency and shape parameters. The results of this analysis lead to the conclusion that parallelism between zero interaction combination and single-agent dose-response relations is found only for special cases and cannot be used as a general criterion for defining zero-interaction in combined-action assessment even if the correct potency shift is taken into account.


Screening of new huprines--inhibitors of acetylcholinesterases by electrospray ionization ion trap mass spectrometry.
Acetylcholinesterase inhibitors (AChEI) are one of the drugs families validated for clinical use in the treatment of Alzheimer's disease (AD). For this reason, finding new more potent and more selective AChEIs is always of interest. Since 1961, the inhibitory activity of AChEI is evaluated through the Ellman's method. Herein, we reported a MS-based evaluation of potential new AChEI with the determination of their inhibitory activity (IC(50) and K(I)). Compared to the Ellman's method, that uses the substrate analog acetylthiocholine, the electrospray ionization ion trap mass spectrometry (ESI-IT-MS) consists in monitoring the conversion ratio of a low concentration of the natural substrate - acetylcholine to choline. We present here the inhibition activity of huprine X and six of its derivates (bearing different functional groups at position 9) towards the recombinant human (rhAChE) and Electrophorus electricus acetylcholinesterase (EelAChE). Mechanisms of action of selected inhibitors were evaluated by means of Lineweaver-Burk plot analysis. The Michaelis-Menten constants (K(M)), inhibitory constants (K(I)) were examined as well as the IC(50) to allow classifying a series of huprine derivatives by inhibition potency by a comparison with a reference (huprine X). Our results demonstrate that these drugs are very potent AChE inhibitors, especially (±)-huprine 6 with an inhibitory activity on recombinant human AChE (rhAChE) in the picomolar range. This study reveals the interest of huprine compounds in the treatment of AD.


Ocular and cerebral ischemic mechanisms in disease of the internal carotid artery.
Stenosis of the internal carotid artery reduces the flow velocity in the ophthalmic artery. Lowered velocity permits increased red cell aggregation and decreased red cell deformability which increases viscosity. Contrary to the theory of remotely originating emboli, this is an alternate hypothesis regarding transient attacks of ocular and cerebral ischemia. The ophthalmic artery circulation time was measured in two groups of patients. The circulation time was defined as the interval between the appearance of contrast media in the siphon of the internal carotid artery and in the ocular choroid. The measurement was made on 151 angiograms of 108 subjects. These vessels were normal. An additional 76 patients had 108 angiograms which showed various amounts of internal carotid artery stenosis. These 76 patients had transient ischemic attacks; retinal, cerebral, or both. There is a significant difference in the ophthalmic artery circulation time in the two groups. The slowing in the ophthalmic artery is related to the degree of internal carotid artery narrowing. The circulation time in a cerebral branch of the internal carotid was not measured. It is presumed that stenosis of the internal carotid artery would have the same effect on a cerebral artery as on the ophthalmic artery.


Role of AC-cAMP-PKA Cascade in Antidepressant Action of Electroacupuncture Treatment in Rats.
Adenylyl cyclase (AC)-cyclic adenosine monophosphate (cAMP)-cAMP-dependent protein kinase A (PKA) cascade is considered to be associated with the pathogenesis and treatment of depression. The present study was conducted to explore the role of the cAMP cascade in antidepressant action of electroacupuncture (EA) treatment for chronic mild stress (CMS)-induced depression model rats. The results showed that EA improved significantly behavior symptoms in depression and dysfunction of AC-cAMP-PKA signal transduction pathway induced by CMS, which was as effective as fluoxetine. Moreover, the antidepressant effects of EA rather than Fluoxetine were completely abolished by H89, a specific PKA inhibitor. Consequently, EA has a significant antidepressant treatment in CMS-induced depression model rats, and AC-cAMP-PKA signal transduction pathway is crucial for it.


[Hodgkin Lymphoma].
Hodgkin lymphoma affect about 1500 new patients annually in France and 60% of the patients presented a localized disease. HL is highly curable with chemotherapy such as ABVD and escalated BEACOPP and for limited stage, consolidation with involved-field or involved nodes radiation therapy. Treatment could be optimized using positron emission tomography (PET) scan performed after 2 cycles to identify early responders and PET2 positive patients who are at high risk of relapse. Hodgkin lymphoma is characterized a minority of malignant Hodgkin and Reed-Sternberg (HRS) cells and a predominance of inflammatory cells. HRS cells could be targeted by antibody drug conjugates targeting CD30 showing a strong efficacy for relapsed patients. Monoclonal antibodies that are directed against the immune checkpoints especially the PD-1- PD-L1/L2 axis showed also a significant activity for patients relapsing after brentuximab vedotin and autograft. These targeted drugs are currently testing in clinical trials in early phase of the disease.


Otoprotective effects of mouse nerve growth factor in DBA/2J mice with early-onset progressive hearing loss.
As it displays progressive hair-cell loss and degeneration of spiral ganglion neurons (SGNs) characterized by early-onset progressive hearing loss (ePHL), DBA/2J is an inbred mouse strain widely used in hearing research. Mouse nerve growth factor (mNGF), as a common exogenous nerve growth factor (NGF), has been studied extensively for its ability to promote neuronal survival and growth. To determine whether mNGF can ameliorate progressive hearing loss (PHL) in DBA/2J mice, saline or mNGF was given to DBA/2J mice of either sex by daily intramuscular injection from the 1st to the 9th week after birth. At 5, 7, and 9 weeks of age, in comparison with vehicle groups, mNGF groups experienced decreased auditory-evoked brainstem response (ABR) thresholds and increased distortion product otoacoustic emission (DPOAE) amplitudes, the prevention of hair cell loss, and the inhibition of apoptosis of SGNs. Downregulation of Bak/Bax and Caspase genes and proteins in cochleae of mice receiving the mNGF treatment was detected by real-time PCR, Western blot, and immunohistochemistry. This suggests that the Bak-dependent mitochondrial apoptosis pathway may be involved in the otoprotective mechanism of mNGF in progressive hearing loss of DBA/2J mice. Our results demonstrate that mNGF can act as an otoprotectant in the DBA/2J mice for the early intervention of PHL and, thus, could become of great value in clinical applications. © 2017 Wiley Periodicals, Inc.


[Expression and action of hepatic sterol regulatory element-binding protein-1c in patients with nonalcoholic fatty liver disease].
To investigate the hepatic expression of sterol regulatory element-binding proteins-1c (SREBP-1c) in patients with nonalcoholic fatty liver disease (NAFLD). NAFLD patients were confirmed using clinical and pathological methods. The expressions of protein and mRNA of SREBP-1 c in the livers were detected by immunohistochemistry, reverse transcription and polymerase chain reactions. The expression of protein of fatty acid synthases (FAS) controlled by SREBP-1c was observed by immunofluorescence. Levels of triglyceride and cholesterol in serum were measured. The serum levels of triglyceride and cholesterol were positively correlated with hepatic adipose degeneration (r=0.71 or 0.70, P less than 0.05). The levels of SREBP-1c protein in the livers of NAFLD patients were significantly higher than those of the control group (2.19+/-0.31 vs 1.15+/-0.20, t=11.06, P less than 0.05), and the more severe the fatty degeneration, the stronger their expression (F=24.54, P less than 0.01). The expressions of the SREBP-1C mRNA in the livers showed the same changes (0.69+/-0.02 vs 0.40+/-0.02, t= -14.63, P less than 0.05). The expression of FAS was enhanced significantly in the livers of the NAFLD patients. Enhanced expression of SREBP-1 c and FAS maybe a factor causing hepatic lipopexia in NAFLD patients.


The Aberrant Expression of the Mesenchymal Variant of FGFR2 in the Epithelial Context Inhibits Autophagy.
Signaling of the epithelial splice variant of fibroblast growth factor receptor 2 (FGFR2b) triggers both differentiation and autophagy, while the aberrant expression of the mesenchymal FGFR2c isoform in epithelial cells induces impaired differentiation, epithelial mesenchymal transition (EMT) and tumorigenic features. Here we analyzed in the human keratinocyte cell line, as well as in primary cultured cells, the possible impact of FGFR2c forced expression on the autophagic process. Biochemical and quantitative immunofluorescence analysis, coupled to the use of autophagic flux sensors, specific substrate inhibitors or silencing approaches, showed that ectopic expression and the activation of FGFR2c inhibit the autophagosome formation and that AKT/MTOR is the downstream signaling mainly involved. Interestingly, the selective inhibition of AKT or MTOR substrates caused a reversion of the effects of FGFR2c on autophagy, which could also arise from the imbalance of the interplay between AKT/MTOR pathway and JNK1 signaling in favor of JNK1 activation, BCL-2 phosphorylation and possibly phagophore nucleation. Finally, silencing experiments of depletion of ESRP1, responsible for FGFR2 splicing and consequent FGFR2b expression, indicated that the switching from FGFR2b to FGFR2c isoform could represent the key event underlying the inhibition of the autophagic process in the epithelial context. Our results provide the first evidence of a negative impact of the out-of-context expression of FGFR2c on autophagy, suggesting a possible role of this receptor in the modulation of the recently proposed negative loop between autophagy and EMT during carcinogenesis.


Hemoglobin variability: impact on anemia management practices.
Data indicate that a wide range of factors can contribute to inter- and intrapatient variability in hemoglobin (Hb) levels in dialysis patients. Some of these factors are controllable and can be minimized by implementing nursing practices that encourage consistent and accurate Hb assessments and management. However, many of these factors are difficult or impossible to modify, and natural intrapatient variations are therefore expected and unavoidable. When natural variability leads to Hb levels that temporarily exceed 12 g/dL, appropriate protocol-guided nursing responses should include long-term, patient-specific laboratory trend analyses, data-driven adjustments in the anemia management prescription, and accurate nursing documentation of assessments, interventions, and outcomes.


Zinc-α2-glycoprotein is associated with non-albuminuric chronic kidney disease progression in type 2 diabetes: a retrospective study with 4-year follow-up.
To investigate the association between baseline plasma zinc-α2-glycoprotein and non-albuminuric chronic kidney disease progression in type 2 diabetes. Adults with normoalbuminuria at entry (n=341; age 57±10 years, 52% men) were analysed. Chronic kidney disease progression was defined as a decrease in chronic kidney disease stage and a decline of ≥25% in estimated GFR from baseline. Baseline plasma zinc-α2-glycoprotein levels were quantified by immunoassay, and analysed either as a continuous variable or by tertiles in Cox proportional hazards models. Model discrimination was assessed using Harrell's C-index. A sensitivity analysis was performed on a subset of individuals who maintained normoalbuminuria during follow-up. Chronic kidney disease progression occurred in 54 participants (16%). Zinc-α2-glycoprotein levels were elevated in chronic kidney disease progressors (P = 0.011), and more progressors were assigned to the higher zinc-α2-glycoprotein tertile than non-progressors. In the unadjusted Cox model, zinc-α2-glycoprotein, both as a continuous variable (hazard ratio 1.72, 95% CI 1.08-2.75) and tertile 3 (vs tertile 1; hazard ratio 2.14, 95% CI 1.10-4.17), predicted chronic kidney disease progression. The association persisted after multivariable adjustment. The C-index of the Cox model increased significantly after incorporation of zinc-α2-glycoprotein into a base model comprising renin-angiotensin system antagonist usage. Sensitivity analysis showed that zinc-α2-glycoprotein independently predicted chronic kidney disease progression among individuals who maintained normoalbuminuria during follow-up. Plasma zinc-α2-glycoprotein is associated with chronic kidney disease progression, and may serve as a useful early biomarker for predicting non-albuminuric chronic kidney disease progression in type 2 diabetes.


Directed transfer of microwave radiation in sliding-mode plasma waveguides produced by ultraviolet laser in atmospheric air.
Experiments have been performed at hybrid Ti:sapphire/KrF laser facility GARPUN-MTW to develop a novel technique to create a hollow-core sliding-mode plasma-filament waveguide for directed transfer of microwave radiation. Efficient multiphoton air ionization was produced by a train of picosecond 1-TW UV pulses at 248 nm wavelength, or by amplitude-modulated 100 ns pulse combining a short-pulse train with a free-running 1-GW pulse, which detached electrons off O2- ions. Multiple filamentation of UV laser radiation in air was observed, and filamentation theory based on resonance-enhanced ionization was developed to explain the experimental results.


Open innovation: Towards sharing of data, models and workflows.
Sharing of resources across organisations to support open innovation is an old idea, but which is being taken up by the scientific community at increasing speed, concerning public sharing in particular. The ability to address new questions or provide more precise answers to old questions through merged information is among the attractive features of sharing. Increased efficiency through reuse, and increased reliability of scientific findings through enhanced transparency, are expected outcomes from sharing. In the field of pharmacometrics, efforts to publicly share data, models and workflow have recently started. Sharing of individual-level longitudinal data for modelling requires solving legal, ethical and proprietary issues similar to many other fields, but there are also pharmacometric-specific aspects regarding data formats, exchange standards, and database properties. Several organisations (CDISC, C-Path, IMI, ISoP) are working to solve these issues and propose standards. There are also a number of initiatives aimed at collecting disease-specific databases - Alzheimer's Disease (ADNI, CAMD), malaria (WWARN), oncology (PDS), Parkinson's Disease (PPMI), tuberculosis (CPTR, TB-PACTS, ReSeqTB) - suitable for drug-disease modelling. Organized sharing of pharmacometric executable model code and associated information has in the past been sparse, but a model repository (DDMoRe Model Repository) intended for the purpose has recently been launched. In addition several other services can facilitate model sharing more generally. Pharmacometric workflows have matured over the last decades and initiatives to more fully capture those applied to analyses are ongoing. In order to maximize both the impact of pharmacometrics and the knowledge extracted from clinical data, the scientific community needs to take ownership of and create opportunities for open innovation.


Fibroblast growth factor receptors, developmental corruption and malignant disease.
Fibroblast growth factors (FGF) are a family of ligands that bind to four different types of cell surface receptor entitled, FGFR1, FGFR2, FGFR3 and FGFR4. These receptors differ in their ligand binding affinity and tissue distribution. The prototypical receptor structure is that of an extracellular region comprising three immunoglobulin (Ig)-like domains, a hydrophobic transmembrane segment and a split intracellular tyrosine kinase domain. Alternative gene splicing affecting the extracellular third Ig loop also creates different receptor isoforms entitled FGFRIIIb and FGFRIIIc. Somatic fibroblast growth factor receptor (FGFR) mutations are implicated in different types of cancer and germline FGFR mutations occur in developmental syndromes particularly those in which craniosynostosis is a feature. The mutations found in both conditions are often identical. Many somatic FGFR mutations in cancer are gain-of-function mutations of established preclinical oncogenic potential. Gene amplification can also occur with 19-22% of squamous cell lung cancers for example having amplification of FGFR1. Ontologic comparators can be informative such as aberrant spermatogenesis being implicated in both spermatocytic seminomas and Apert syndrome. The former arises from somatic FGFR3 mutations and Apert syndrome arises from germline FGFR2 mutations. Finally, therapeutics directed at inhibiting the FGF/FGFR interaction are a promising subject for clinical trials.


Speckle variance detection of microvasculature using swept-source optical coherence tomography.
We report on imaging of microcirculation by calculating the speckle variance of optical coherence tomography (OCT) structural images acquired using a Fourier domain mode-locked swept-wavelength laser. The algorithm calculates interframe speckle variance in two-dimensional and three-dimensional OCT data sets and shows little dependence to the Doppler angle ranging from 75 degrees to 90 degrees . We demonstrate in vivo detection of blood flow in vessels as small as 25 microm in diameter in a dorsal skinfold window chamber model with direct comparison with intravital fluorescence confocal microscopy. This technique can visualize vessel-size-dependent vascular shutdown and transient vascular occlusion during Visudyne photodynamic therapy and may provide opportunities for studying therapeutic effects of antivascular treatments without on exogenous contrast agent.


Combining the GP's assessment and the PHQ-9 questionnaire leads to more reliable and clinically relevant diagnoses in primary care.
Screening questionnaires are not sufficient to improve diagnostic quality of depression in primary care. The additional consideration of the general practitioner's (GP's) assessment could improve the accuracy of depression diagnosis. The aim of this study was to examine whether the GP rating supports a reliable depression diagnosis indicated by the PHQ-9 over a period of three months. We performed a secondary data analysis from a previous study. PHQ-9 scores of primary care patients were collected at the time of recruitment (t1) and during a follow-up 3 months later (t2). At t1 GPs independently made a subjective assessment whether they considered the patient depressive (yes/no). Two corresponding groups with concordant and discordant PHQ-9 and GP ratings at t1 were defined. Reliability of the PHQ-9 results at t1 and t2 was assessed within these groups and within the entire sample by Cohen's Kappa, Pearson's correlation coefficient and Bland-Altman plots. 364 consecutive patients from 12 practices in the region of Upper Bavaria/Germany participated in this longitudinal study. 279 patients (76.6%) sent back the questionnaire at t2. Concordance of GP rating and PHQ-9 at t1 led to higher replicability of PHQ-9 results between t1 and t2. The reliability of PHQ-9 was higher in the concordant subgroup (κ = 0.507) compared to the discordant subgroup (κ = 0.211) (p = 0.064). The Bland-Altman Plot showed that the deviation of PHQ-9 scores at t1 and t2 decreased by about 15% in the concordant subgroup. Pearson's correlation coefficient between PHQ-9 scores at t1 and t2 increased significantly if the GP rating was concordant with the PHQ-9 at t1 (r = 0.671) compared to the discordant subgroup (r = 0.462) (p = 0.044). The combination of PHQ-9 and GP rating might improve diagnostic decision making regarding depression in general practices. PHQ-9 positive results might be more reliable and accurate, when a concordant GP rating is considered.


Thyroid function during pregnancy in women with past Graves' disease.
Graves' disease and thyroid dysfunction during pregnancy can lead to maternal and fetal complications. No information is available on thyroid function in women with a past history of Graves' disease. We compared free T3, free T4 and TSH in a group of pregnant women with a history of resolved Graves' disease requiring no current treatment (n= 34) and in a group of pregnant controls (n= 102). We found no significant differences in the levels of these hormones between the two groups. Women with a past history of Graves' disease and no current treatment display a normal thyroid function and adaptation during pregnancy.


Outcomes among youth attending inpatient treatment for co-occurring disorders.
An emerging body of research is identifying effective outpatient integrated treatment approaches for youth with co-occurring psychiatric and substance use disorders, though few studies exist examining inpatient treatment. The current study aimed to address this gap by examining response to treatment during admission to, and in the year following discharge from, a specialized inpatient program for youth with co-occurring disorders. A single-cohort longitudinal design examined change in adaptive functioning, mental health symptoms, and substance use frequency among N = 142 youth (69.1% female) aged 14-21 (M = 16.9, SD = 1.5) attending the program. Participants completed self-report measures at admission, discharge, and 1-, 6- and 12-months post-discharge. Analyses indicated significant improvements in adaptive functioning, internalizing and externalizing symptoms, and substance use frequency during admission. There was some loss of gains in adaptive functioning over the 12-months post-discharge. Improvements were maintained in internalizing symptoms and substance use frequency, and improvements in externalizing symptoms continued over the 12-months post-discharge. There was no significant interaction between change in functioning and internalizing symptoms at admission or type of substance use disorder diagnosis. There was a significant interaction with externalizing symptoms, such that those with clinically significant levels of externalizing symptoms at admission experienced greater improvement in functioning, though the groups ended treatment with comparable functioning scores. The results provide preliminary support for integrated treatment for co-occurring disorders delivered in an inpatient setting. However, the results also reflect the significant needs of youth with co-occurring disorders and the importance of ongoing care post-discharge from intensive treatment settings.


A comparison of frequency and sources of nursing job stress perceived by intensive care, hospice and medical-surgical nurses.
This study compared the frequency and sources of nursing job stress perceived by 35 intensive care (ICU), 30 hospice and 73 medical-surgical nurses. Analysis of variance revealed no significant differences among the three groups of nurses on the overall frequency of job stress. Post-hoc Tukey tests demonstrated a significant difference in three stress subscales among the three groups. ICU and hospice nurses perceived significantly more stress than medical-surgical nurses related to death and dying; ICU and medical-surgical nurses perceived significantly more stress than hospice nurses related to floating; and medical-surgical nurses perceived significantly more stress than ICU and hospice nurses related to work-overload/staffing. Spearman-Rank Correlation revealed no significant correlations among the three groups in their rank-ordering of the eight stress subscales. Death and dying situations were the most stressful to ICU and hospice nurses, while work-overload/staffing situations were the most stressful to medical-surgical nurses. Results of the study, although not generalizable, have implications for nurse managers.


Transition from carbonatitic magmas to hydrothermal brines: Continuous dilution or fluid exsolution?
Carbonatites are the most important primary sources for the rare earth elements (REEs). While fractional crystallization of carbonate minerals results in the enrichment of volatiles, alkalis, and REEs in the remaining melts, the transition from carbonatitic magmas to hydrothermal brines remains unclear. Here, we investigated the pressure-temperature-composition (P-T-X) properties of the Na2CO3-H2O system up to 700°C and 11.0 kbar using a hydrothermal diamond anvil cell and a Raman spectrometer. Our results show that Na2CO3 becomes increasingly soluble under high P-T conditions, leading to the disappearance of melt-fluid immiscibility and the continuous transition from Na2CO3 melts to hydrothermal brines under deep crustal conditions. Given the abundance of Na2CO3 in highly evolved carbonatitic systems, we suggest that the continuous melt-fluid transition in deep-seated carbonatites results in REEs being sufficiently concentrated in the brine-melts to form economic ore bodies, whereas in shallow systems, REEs preferentially partition into carbonatitic magmas over synmagmatic brines and disperse in carbonatite rocks that underwent limited fractionation.


Purification and characterization of the RNase H domain of HIV-1 reverse transcriptase expressed in recombinant Escherichia coli.
The ribonuclease H (RNase H) domain of human immuno-deficiency virus (HIV-1) reverse transcriptase has been produced with the aim of providing sufficient amounts of protein for biophysical studies. A plasmid vector is described which directs high level expression of the RNase H domain under the control of the lambda PL promoter. The domain corresponds to residues 427-560 of the 66 kDa reverse transcriptase. The protein was expressed in Escherichia coli and was purified using ion-exchange and size exclusion chromatography. The purified protein appears to be in a native-like homogeneous conformational state as determined by 1H-NMR spectroscopy and circular dichroism measurements. HIV-protease treatment of the RNase H domain resulted in cleavage between Phe-440 and Tyr-441.


Trehalose sustains a higher post-thaw sperm motility than sucrose in vitrified human sperm.
One of the cryopreservation methods that best preserves sperm function is vitrification. However, comparative studies have not been performed to evaluate the effect of nonpermeable cryoprotectors on sperm function for prolonged periods of time post-devitrification. These times are necessary, especially in in vitro fertilisation and intrauterine insemination, for gamete interaction and then fertilisation to occur, while maintaining motility to arrive at the fertilisation site. In this study, sucrose (.25 m) and trehalose (.1 and .05 m) were compared in essential parameters like motility and plasma membrane integrity for 12 hr. Post-devitrification sperm motility using .1 m trehalose was 68.9%, higher than that obtained with .05 m trehalose (59.9%, p < .0081) and .25 m sucrose (57.9%, p < .0002). Similar results were obtained at 6 and 12 hr with .1 m trehalose (58.0% and 42.3% respectively) compared to .05 m trehalose (p < .0184 and p < .033) and .25 m sucrose (p < .0001 and p < .0012).There was no difference between .25 m sucrose and .05 m trehalose. Membrane integrity was best preserved at time 0 by .1 m trehalose (p < .05), but there was no significance at 6 and 12 hr compared to sucrose. Our results suggest that for assisted reproduction techniques that require motile spermatozoa for a longer period of time, use of .1 m trehalose is recommended in the sperm vitrification technique.


Lack of Evidence for erm(B) Infiltration Into Erythromycin-Resistant Campylobacter coli and Campylobacter jejuni from Commercial Turkey Production in Eastern North Carolina: A Major Turkey-Growing Region in the United States.
In Campylobacter spp., resistance to erythromycin and other macrolides has typically implicated ribosomal mutations, especially substitutions in the 23S rRNA genes. However, in 2014, the macrolide resistance gene erm(B) was reported for the first time in Campylobacter and shown to be harbored by a multidrug resistance island in the chromosome of the swine-derived strain Campylobacter coli ZC113. erm(B)-positive C. coli and Campylobacter jejuni strains from the food supply have been mostly reported from China. However, erm(B)-positive C. coli isolates were also detected recently in fecal samples from turkeys in Spain. To determine whether erm(B) may be harbored by erythromycin-resistant Campylobacter from commercial turkey production in eastern North Carolina, a major turkey-growing region in the United States, we investigated a panel of 178 erythromycin-resistant isolates (174 C. coli, 4 C. jejuni) using PCR with erm(B)-specific primers. None of the isolates were PCR-positive for erm(B) and sequence analysis of a subset of these erythromycin-resistant isolates revealed that all harbored A2075G substitutions in the 23S rRNA genes. Data fail to provide evidence for infiltration of erm(B) into erythromycin-resistant Campylobacter from commercial turkey production in this region and suggest the need for continuing surveillance.


Peptide-amidating enzymes are expressed in the stellate epithelial cells of the thymic medulla.
C-terminal amidation is a post-translational processing step necessary to convey biological activity to a large number of regulatory peptides. In this study we have demonstrated that the peptidyl-glycine alpha-amidating monooxygenase enzyme complex (PAM) responsible for this activity is located in the medullary stellate epithelial cells of the thymus and in cultured epithelial cells bearing a medullary phenotype, using Northern blot, immunocytochemistry, in situ hybridization, and enzyme assays. Immunocytochemical localization revealed a granular pattern in the cytoplasm of the stellate cells, which were also positive for cytokeratins and a B-lymphocyte-associated antigen. The presence of PAM activity in medium conditioned by thymic epithelial cell lines suggests that PAM is a secreted product of these cells. Among the four epithelial cell lines examined, there was a direct correlation between PAM activity and content of oxytocin, an amidated peptide. Taken together, these data provide convincing evidence that thymic epithelial cells have the capacity to generate amidated peptides that may influence T-cell differentiation and suggest that the amidating enzymes could play an important role in the regulation of thymic physiology.


CARDIAC SURGERY FOR VALVULAR HEART DISEASE AT A REFERRAL HOSPITAL IN ETHIOPIA: A REVIEW OF CASES OPERATED IN THE LAST 30 YEARS.
Valvular heart disease has been a significant cause of heart disease worldwide. In Ethiopia, it particularly affects young individuals and constitutes the major cause of cardiovascular disease. Factors associated with choice of treatment for advanced valvular heart disease are variable. The objective of this study is to review surgery done for Ethiopian patients with valvular heart disease. We analyzed data on patients who had valve surgery and follow-up at the Tikur Anbessa Specialized Hospital cardiology unit. We collected data on sociodemographic characteristics, the pre-operative status of effected valves and co-morbidities, and assessed their associations with patient management options. A total of 157 valve surgeries were done from 1983 to 2013. Mean age at time of surgery was 26.7 years and females constituted 66% of the cases. Patients with rheumatic heart disease were younger, more likely to be female and have atrial fibrillation, but less likely to have impaired left ventricular systolic function when compared to patients with non-rheumatic heart disease. More than 75% of the surgical procedures done were mechanical valve replacement. Mechanical valves, compared with bioprosthetic valves, were more likely to be used in patients with rheumatic heart disease. The median age of those receiving mechanical valves, 24 (IQR 22-28) years, was lower than those receiving bioprosthetic valves, 31.5 (IQR 29.9-37.9) years. Mechanical valve replacement was significantly higher in those under the age of 20 years (Adjusted Odds Ratio 41.0, 95% CI: 3.0-557.2) and in those between 20 and 29 years of age (Adjusted Odds Ratio 14.3, 95% CI: 2.3-88.6). Valve surgery for valvular heart diseases has been more common performed for young and female patients. A great majority of the replacements done have been with mechanical valves. As many of the patients have been younger and female, the choice of valve surgery and the need for anticoagulation impacts subsequent management of rheumatic heart disease and associated morbidities, lifestyle plans and pregnancy.


Effects of hyperthyroidism on rat liver glutathione metabolism: related enzymes' activities, efflux, and turnover.
The effect of hyperthyroidism on liver glutathione (GSH) metabolism was studied in fed rats after the administration of 0.1 mg T3/kg body wt, for 1-3 consecutive days. T3-calorigenesis resulted in elevated rates of O2 consumption by the liver, together with higher lipid peroxidative processes and GSH depletion, compared to the euthyroid state. The study of the enzymes related to GSH metabolism revealed no significant changes in the activity of glutathione peroxidase and glutathione reductase, with decreases (27-41%) in the activity of glutathione-S-transferases and marked elevation (133%) in that of gamma-glutamyl transferase, 3 days after T3 treatment. At this experimental time, the activity of the NADPH generating enzyme glucose-6-phosphate dehydrogenase was enhanced by 84% in the liver of T3-treated rats, compared to that in the controls. In these conditions, the canalicular efflux of GSH was not altered by T3, whereas net and fractional rates of sinusoidal GSH efflux were enhanced by 86% and 288%, respectively. The latter effect of hyperthyroidism was found in parallel with an enhancement in sinusoidal lactate dehydrogenase and protein release, suggesting that loss of GSH might be related to a permeabilization of the hepatocyte plasma membrane. Liver GSH turnover assessed after a pulse of [35S]cysteine resulted in a 209% increase in the fractional turnover rate in hyperthyroid rats over controls, under steady state conditions for both hepatic GSH pools, leading to a 62% enhancement in the respective turnover flux. Data suggest that the elevation in the sinusoidal GSH efflux from the liver and in the hepatic capacity to degrade the tripeptide are major mechanisms leading to GSH depletion in the liver of T3-treated rats. As the increased GSH use is not balanced by the elevation in GSH synthesis, a lower steady state level of GSH is attained in the liver.


Effects of asiaticoside on levels of podocyte cytoskeletal proteins and renal slit diaphragm proteins in adriamycin-induced rat nephropathy.
Centella asiatica has been used to treat kidney diseases in Chinese traditional medicine. Asiaticoside (an extraction of C. asiatica) exerts a variety of pharmacological effects including immunomodulatory and anti-inflammatory functions. However, the mechanism of asiaticoside in the treatment of renal diseases remains largely unknown. This study investigated the molecular mechanism of asiaticoside in treating adriamycin-induced nephropathy of rats. Sixty-two SD male rats were randomly divided into normal control group (n=12) and nephropathy group (n=50). Except for the normal control group, rats were injected with adriamycin (6mg/kg) via the tail vein to induce nephropathy. Adriamycin induced nephropathic rats were divided into untreated group, prednisone group (25mg/kg), and asiaticoside groups with various dosages (8, 16 and 32mg/kg). Samples of urine and serum, tissue of kidney were collected for analysis after treatments for four weeks. Morphological changes were evaluated under light microscope and electron microscope. Synaptopodin, desmin, nephrin and podocin mRNA and protein were determined by RT-PCR and Western blotting. Compared to the untreated nephropathy group, asiaticoside treatment mitigated histological damages, decreased 24-hour urine protein excretion and total cholesterol, increased serum albumin. Asiaticoside treatment increased the mRNA and protein levels of synaptopodin, nephrin and podocin in a dose-dependent manner. Furthermore, asiaticoside treatment decreased the mRNA and protein levels of desmin. Asiaticoside can mitigate adriamycin-induced nephropathy in rats, which is associated with the increase in synaptopodin, nephrin and podocin gene expression, and the decrease in desmin gene expression.


Theoretical study of the reaction of acrylonitrile on Si(001).
Two recent experiments for adsorbed acrylonitrile on the Si(001) surface reported different adsorption structures at 110 and 300 K. We investigate the reaction of acrylonitrile on Si(001) by first-principles density-functional calculations. We find that the so-called [4+2] structure in which acrylonitrile resides between two dimer rows is not only thermodynamically favored over other structural models but also easily formed via a precursor where the N atom of acrylonitrile is attached to the down atom of the Si dimer. The additional initial-state theory calculation for the C 1s core levels of adsorbed acrylonitrile provides an interpretation for the observed low- and room-temperature adsorption configurations in terms of the precursor and [4+2] structures, respectively.


Protective roles of sodium selenite against aflatoxin B1-induced apoptosis of jejunum in broilers.
The effects of aflatoxin B1 (AFB1) exposure and sodium selenite supplementation on cell apoptosis of jejunum in broilers were studied. A total of 240 one-day-old male AA broilers were randomly assigned four dietary treatments containing 0 mg/kg of AFB1 (control), 0.3 mg/kg AFB1 (AFB1), 0.4 mg/kg supplement Se (+ Se) and 0.3 mg/kg AFB1 + 0.4 mg/kg supplement Se (AFB1 + Se), respectively. Compared with the control broilers, the number of apoptotic cells, the expression of Bax and Caspase-3 mRNA were significantly increased, while the expression of Bcl-2 mRNA and the Bcl-2/Bax ratio were significantly decreased in AFB1 broilers. The number of apoptotic cells and the expression of Caspase-3 mRNA in AFB1 + Se broilers were significantly higher than those in the control broilers, but significantly lower than those in AFB1 broilers. There were no significant changes in the expression of Bax mRNA between AFB1 + Se and control broilers; the expression of Bcl-2 mRNA and the Bcl-2/Bax ratio in AFB1 + Se broilers were significantly lower than those in the control broilers, but significantly higher than those in AFB1 broilers. In conclusion, 0.3 mg/kg AFB1 in the diet can increase cell apoptosis, decrease Bcl-2 mRNA expression, and increase of Bax and Caspase-3 mRNA expression in broiler's jejunum. However, supplementation of dietary sodium selenite at the concentration of 0.4 mg/kg Se may ameliorate AFB1-induced apoptosis by increasing Bcl-2 mRNA expression, and decreasing Bax and Caspase-3 mRNA expression.


A new strategy for the synthesis of benzylic sulfonamides: palladium-catalyzed arylation and sulfonamide metathesis.
An efficient two-step strategy has been developed to access diversely functionalized benzylic sulfonamides. Execution of this strategy required the development of two reaction methods: the palladium-catalyzed cross-coupling of aryl halides with CH-acidic methanesulfonamides and a metathesis reaction between the resulting alpha-arylated sulfonamides and diverse amines. The broad scope of the cross-coupling process combined with a versatile sulfonamide metathesis constitutes an efficient strategy for the synthesis of various benzylic sulfonamides.


Cranial computed tomography in Whipple's disease.
Cranial computed tomography (CT) in a 58-year-old man disclosed enhancing lesions in the medial right temporal lobe and the right pons. Biopsy of the sural nerve was positive for Whipple's disease, and one of the temporal lobe lesions showed unprecedented histological findings. This case, to our knowledge, is unique in its demonstration of cranial CT findings in association with Whipple's disease. It is suggested that a cranial CT scan with the use of intravenous contrast material should be performed in patients presenting with the signs or symptoms of Whipple's disease.


Outcomes in Symptomatic Patients With Vertebrobasilar Dolichoectasia Following Endovascular Treatment.
Objective: To evaluate whether the presenting symptoms of VBD predict outcomes following endovascular treatment. Methods: We retrospectively reviewed our institutional clinical database and identified 22 patients (all men; mean age: 52.6 years, range: 11-73 years) with a diagnosis of VBD, who underwent endovascular treatment from January 2010 to December 2017. Results: After analyzing the clinical and imaging data, we evaluated data for 22 symptomatic patients with VBD. At the time of VBD diagnosis, 13 patients (59%) had compressive symptoms, four (18%) had hemorrhagic symptoms, and five (23%) had ischemic symptoms. Nine of the 22 patients (41%), who presented with hemorrhagic and ischemic symptoms, achieved a satisfactory clinical and/or digital subtraction angiography imaging outcome after endovascular treatment. However, of the 13 patients who presented with compressive symptoms, seven (54%, 7/13) died from severe brainstem compression during follow-up; furthermore, magnetic resonance imaging showed worsening of the mass effect in eight patients with compressive symptoms (62%, 8/13). Conclusions: VBD is considered a challenging lesion without an ideal treatment modality. Endovascular treatment of VBD in patients presenting with compressive symptoms at diagnosis may not be beneficial. However, long-term outcomes following endovascular treatment may be acceptable in patients with non-compressive symptoms at diagnosis compared with those with compressive symptoms.


Tachysystole and risk of cesarean section after labor induction using misoprostol: A cohort study.
To investigate if tachysystole was associated with an increased risk of cesarean section or unfavorable maternal or neonatal outcomes following induction of labor by misoprostol vaginal inserts. We conducted a retrospective cohort study of 446 women over 37 weeks of gestation admitted for labor induction by misoprostol vaginal inserts between May 2016 and May 2017. Fetal heart rate and uterine activity tracings were assessed for tachysystole, defined as ≥ 6 contractions per 10 min, averaged over a 30-minute window. Univariate analysis was performed by using t-test and Chi-square, comparing demographics, pregnancy characteristics, intrapartum monitoring, mode of delivery, neonatal outcomes (Apgar score < 7 at 5 min, umbilical cord artery pH < 7.10, neonatal intensive care unit admission) and maternal outcomes, with regard to the presence of tachysystole. The association between tachysystole and cesarean section was evaluated after adjusting for potential confounders by a modified Poisson regression model, expressed as an adjusted risk ratio and 95 % confidence intervals. A total of 140 women (31.4 %) presented with tachysystole. The median duration of tachysystole was 2 h 12 min. The rate of cesarean section was 25.0 % (N = 35) among patients with tachysystole and 19.6 % (N = 60) for those without tachysystole. Presence of tachysystole during induction of labor with misoprostol vaginal inserts was not associated with cesarean section (adjusted risk ratio,1.0; 95 % confidence interval, 0.7-1.4). Neonatal and maternal outcomes were similar between mothers who did and did not experience tachysystole. This study illustrates that tachysystole is not associated with an increased risk of cesarean section after induction of labor by misoprostol vaginal inserts. The impact of excessive uterine activity on the fetal wellbeing defined by the frequency of uterine contraction alone is probably insufficient. Further research on the development of accurate measures of uterine contractility is necessary to better understand its effect on fetal well-being.


Manganese Ferrite Nanoparticles Encapsulated into Vitamin E/Sphingomyelin Nanoemulsions as Contrast Agents for High-Sensitive Magnetic Resonance Imaging.
Magnetic resonance imaging (MRI) is one of the most powerful non-invasive imaging modalities used in clinics due to its great spatial resolution and excellent soft-tissue contrast, though still less sensitive than other techniques such as the nuclear imaging modalities. This lack of sensitivity can be improved with the use of contrast agents based on nanomaterials. In recent years, researchers have focused on the development of magnetic nanoparticles, given their role as enhancers of the contrast signal based on the magnetic resonance. Manganese ferrite nanoparticles stand out, given their high magnetic susceptibility and magnetic soft nature. Herein, 10 nm MnFe2 O4 nanoparticles, functionalized with the natural antioxidant vitamin E (VitE-MFO) are encapsulated into simple, biodegradable and non-toxic nanoemulsions (NEs), by a reproducible one-step method obtaining stable 150 nm-sized magnetic nanoemulsions (VitE-MFO-NEs). After encapsulation, the superparamagnetic properties of VitE-MFO are maintained and MR imaging studies reveal an extremely high transverse relaxivity for VitE-MFO-NEs (652.9 × 10-3 m-1 s-1 ), twofold higher than VitE-MFO value. Moreover, VitE-MFO-NEs show great in vivo biocompatibility and good signal in in vivo and ex vivo MRI, which indicates their great potential for biomedical imaging enhancing the negative MR contrast and significantly improving the sensitivity of MRI.


Investigations of therapeutic measures for disophenol toxicosis in dogs.
Acute disophenol toxicosis, induced in 10 dogs by giving 33, 35, or 40 mg of disophenol/kg of body weight, was treated with the antipyretic dipyrone, lactated Ringer's infusions, or ice baths. Rectal temperature and estimates of hemoglobin concentration, packed cell volume, and total white blood cell count and differential count were recorded. Higher hemogram values were sometimes observed for dogs dying of the toxicosis. Toxicosis was induced in 5 other dogs which were not treated; 1 of these, given the low dose of disophenol, recovered. Two of 3 dogs (67%) treated with the antipyretic recovered, 0 of 2 (0%) given lactated Ringer's infusion recovered, and 2 of 5 dogs (40%) treated with ice baths recovered. One of the surviving dogs treated with antipyretic was given the low disophenol dose and all the other survivors were given the medium disophenol dosage level.


Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies.
Recently reported risks of colorectal cancer (CRC) in inflammatory bowel disease (IBD) have been lower than those reported before 2000. The aim of this meta-analysis was to update the CRC risk of ulcerative and Crohn's colitis, investigate time trends, and identify high-risk modifiers. The MEDLINE search engine was used to identify all published cohort studies on CRC risk in IBD. Publications were critically appraised for study population, Crohn's disease localization, censoring for colectomy, and patient inclusion methods. The following data were extracted: total and stratified person-years at risk, number of observed CRC, number of expected CRC in background population, time period of inclusion, and geographical location. Pooled standardized incidence ratios and cumulative risks for 10-year disease intervals were calculated. Results were corrected for colectomy and isolated small bowel Crohn's disease. The pooled standardized incidence ratio of CRC in all patients with IBD in population-based studies was 1.7 (95% confidence interval [CI], 1.2-2.2 ). High-risk groups were patients with extensive colitis and an IBD diagnosis before age 30 with standardized incidence ratios of 6.4 (95% confidence interval, 2.4-17.5) and 7.2 (95% confidence interval, 2.9-17.8), respectively. Cumulative risks of CRC were 1%, 2%, and 5% after 10, 20, and >20 years of disease duration, respectively. The risk of CRC is increased in patients with IBD but not as high as previously reported and not in all patients. This decline could be the result of aged cohorts. The risk of CRC is significantly higher in patients with longer disease duration, extensive disease, and IBD diagnosis at young age.


Self-managed learning groups in higher education: students' perceptions of process and outcomes.
Self-managed learning groups are increasingly used in higher education. There is a need for more systematic investigation of university students' perceptions of the processes and outcomes of this learning method. This study aimed to identify the domains of process issues that students perceive as relevant to their participation in self-managed learning groups, and how these processes are perceived to influence group outcomes. Participants were undergraduate psychology students who were members of self-managed learning groups. The first study employed qualitative methods (namely, students' written accounts, interviews, and observation) to study learning groups (N = 180 students) and identify the process domains. In the second study, first and second year students (N = 207) used a questionnaire (based on the domains identified in Study 1) to evaluate the processes and outcomes of their learning groups. Analysis of qualitative data (Study 1) identified seven process domains: task focus, staff support, process learning, environmental fit, managing differences, equity and responsibility, and collaboration and cooperation. Factor analysis of students' responses (Study 2) identified an underlying structure of two process factors: personal responsibility and collaborative climate, and staff support and environmental fit. Both process factors were associated with the self-reported satisfaction and productivity of this group of students. University students' perceptions of the processes of self-managed learning groups have a clear structure. These process factors are associated with perceived group outcomes in systematic and theoretically consistent ways.


Bone response to collagenized xenografts of porcine origin (mp3(®) ) and a bovine bone mineral grafting (4BONE(™) XBM) grafts in tibia defects: experimental study in rabbits.
This study aimed to carry out the evaluation of bone response of new bone formation to two different xenografts (bovine and porcine) biomaterials inserted in rabbit tibiae. The study used a total of 20 male New Zealand albino rabbits. They received a total of 40 grafts in the proximal metaphyseal areas of both tibiae. Two biomaterials were evaluated: 20 porcine xenografts, as a bone granulate (OsteoBiol(®) MP3(®) ; Tecnoss srl, Giaveno, Italy), were placed in the proximal metaphyseal area of the right tibia, 20 anorganic bovine bone mineral grafting (4BONE(™) XBM, MIS Implants Inc., BARLEV, Israel) were placed in the left tibia. Following graft insertion, the animals were sacrificed in two groups of 10 animals, after 1 and 4 months, respectively. For each group, biomaterials were analyzed: newly formed bone, residual graft materials and the connective tissue. Histomorphometric, EDX analysis and element mapping were performed at 1 and 4 months after graft insertion. At 4 months after treatment, the bone defects displayed radiological images that showed complete repair of osseous defects. Histomorphometric evaluation showed that for the porcine xenograft, the study averages for newly formed bone represented 84.23 ± 2.9%, while bovine matrix was 79.34 ± 2.1%. For residual graft material, the porcine biomaterial had 11.23 ± 1.7% and the bovine graft 31.56 ± 2.3%. Finally, the connective tissue for MP3 was 10.33 ± 1.8%, while for the 4BONE(™) XBM we obtained 14.34 ± 2.9%. Element analysis revealed higher percentages of Ca (54 ± 9%) and P (35 ± 6%) in the group B than group A and control group (P < 0.05). Defects of a critical size in a rabbit tibia model can be sealed using a bovine porous biphasic calcium phosphate and MP3 material; this supports new bone formation, creates a bridge between borders, and facilitates bone ingrowth in both biomaterials. Furthermore, this study observed partial dissolution of the mineral phase of four bone graft and complete resorption of porcine MP3 biomaterial and its incorporation into the surrounding bone. Depending on clinical needs, each biomaterial could be useful in daily clinical practice.


On the primary quantum yields in the bacteriorhodopsin photocycle.
Pulsed Nd laser experiments in suspensions of the purple membrane of Halobacterium halobium are carried out at room temperature. At sufficiently high laser intensities, a photostationary mixture of bacteriorhodopsin (BR) and its red-shifted (batho) photoproduct (K) is obtained. The spectra of the first three intermediates in the photocycle are reported. The data yield a value of phi1/phi2=0.40 +/- 0.05 for the ratio of the quantum yields of the forward (phi1) and reverse (phi2) processes, setting an upper limit of approximately 0.4 for the quantum efficiency of the cycle at room temperature. This method is generally available for the determination of phi2 in the case of a photoequilibrium: A in equilibrium B, where B is a short-lived transient and phi1 is known from low intensity measurements. Its potential application is of importance for the study of the photophysics of visual pigments at physiological temperatures.


On the phenotype and development of mutants of early neurogenesis inDrosophila melanogaster.
The central nervous system (CNS) ofDrosophila develops from precursor cells called neuroblasts. Neuroblasts segregate in early embryogenesis from an apparantly undifferentiated ectoderm and move into the embryo, whereas most of the remaining ectodermal cells continue development as epidermal cell precursors. Segregation of neuroblasts occurs within a region called the neurogenic field. We are interested in understanding how the genome ofDrosophila controls the parcelling of the ectoderm into epidermal and neural territories. We describe here mutations belonging to seven complementation groups which effect an abnormal neurogenesis. The phenotypes produced by these mutations are similar. Essential features of these phenotypes are a conspicuous hypertrophy of the CNS accompanied by epidermal defects; the remaining organs and tissues of the mutants are apparently unaffected. The study of mutant phenotype development strongly suggests this phenotype to be due to misrouting into the neural pathway of development of ectodermal cells which in the wildtype would have given rise to epidermal cells, i.e. to an initial enlargement of the neurogenic region at the expense of the epidermogenic region. These observations indicate that the seven genetic loci revealed by the mutations described in this study contribute to control the neurogenic field. The present results suggest that in wildtype development neurogenic genes are supressed within all derivatives of the mesoderm and endoderm and some derivatives of the ectoderm, and conditionally expressed in the remaining ectoderm. The organisation of the neurogenic field in the wildtype is discussed.


Metastasis of soft tissue sarcomas in lymph node: A cytomorphological study.
Soft-tissue sarcoma (STS) rarely metastasizes to lymph node compared to carcinoma. Fine-needle aspiration cytology (FNAC) carries a pivotal role in diagnosis of metastatic tumor to lymph node. This study highlights the role of FNAC in diagnosis of STS metastasis to lymph node. A retrospective study over a period by 4 years carried out. FNAC of enlarged lymph node was performed in patients with STS. Cytology smears were examined in conjunction with clinical details. Histopathology and Immunohistochemistry (IHC) were correlated in synchronous cases. Out of 326 patients, 21 with STS had enlarged lymph nodes, of which 19 cases showed involvement (5.8%). Sixteen cases were metachronous and 3 cases showed synchronous involvement. Fifteen cases had regional lymph nodes while 4 cases had distal lymph node involvement. Head and neck and lower extremities were the most common primary sites of STS. Rhabdomyosarcoma was the most common sarcoma metastasing to the lymph nodes followed by synovial sarcoma, malignant peripheral nerve sheath tumor, and clear cell sarcoma. Other rare tumors included leiomyosarcoma, epitheloid sarcoma, liposarcoma, malignant fibrous histiocytoma, and Ewing's sarcoma/peripheral neuroectodermal tumor. We had a case of dermatofibrosarcoma protuberance (DFSP) of scalp with cervical lymph node metastasis. Very unusual about this case was its rare primary site and the rarer lymph node metastasis. FNAC plays an important role in the diagnosis of lymph node metastasis in cases of STS.


Assessment of the Effect of Phototherapy and PRP on the Immediate Implants: An Original Research.
Immediate implants have been gaining popularity in recent times. There are many adjuvant techniques that are followed before implant placement, which have recently shown hopeful results. For this reason, the current comparative study analyzes the effectiveness of platelet-rich plasma (PRP) and photofunctionalization (PF) at a tertiary care dental hospital. In the current clinical trial, 30 subjects were grouped equally to receive immediate dental implants, with one group in which pretreatment of the extraction site was done with the auto-PRP and PF, while the control group received no pretreatment. For 12 months after the placement of the implant, the subjects were observed for alterations in the parameters. The variables analyzed were survival, esthetics, biological integration, and finally the success of the implants in each group. Values were noted and compared using the appropriate statistical tools, while keeping the level of significance at P < 0.05. For the variables of esthetics and survival, no substantial differences were observed in the PRP and PF groups. There was no difference between these experimental groups and the control group. However, there were significant differences for the biological variable as there was more marginal bone loss in the experimental groups. On the whole, the success was greater for the experimental groups than the control group, though not significant. The pretreatment protocols using PRP and PF have shown to improve some characteristics of the immediate implants in the anterior regions. However, further studies are suggested.


Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase in mice.
Abdominal aortic aneurysm (AAA) is a common disease that, when surgical treatment is inapplicable, results in rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is eagerly awaited, the destruction of the aortic walls in AAA has been considered an irreversible process. We found that c-Jun N-terminal kinase (JNK) is highly activated in human AAA walls. We also found that JNK activity is essential for the expression of matrix metalloproteinase (MMP)-9 and, concurrently, suppression of the extracellular matrix (ECM) biosynthesis. We therefore investigated the role of JNK in the pathogenesis of AAA in vivo. We created a mouse AAA model by periaortic application of CaCl(2), which was accompanied by activation of JNK and MMPs, and suppression of lysyl oxidase (LOX), which is an essential biosynthetic enzyme for collagen and elastin fibers. Our data indicate that, in addition to MMP activities, suppression of ECM biosynthesis may contribute to the AAA pathogenesis because local LOX gene delivery prevented AAA formation. Treatment of mice with SP600125, a specific JNK inhibitor, completely abrogated the formation of CaCl(2)-induced AAA. Furthermore, SP600125 treatment after the establishment of AAA caused a reduction in the aortic diameters with normalized tissue architecture. SP600125 treatment also caused significant regression of angiotensin II-induced AAA in ApoE-null mice after its establishment, as demonstrated by serial ultrasonographic studies in live animals. These data demonstrate that JNK dictates the abnormal ECM metabolism in AAA pathogenesis by enhancing tissue degradation and suppressing tissue repair. Therefore, inhibition of JNK may provide a novel therapeutic option for AAA.


MCL-1 is a clinically targetable vulnerability in breast cancer.
Pro-survival members of the BCL-2 family, including MCL-1, are emerging as important proteins during the development and therapeutic response of solid tumors. Notably, high levels of MCL-1 occur in breast cancer, where functional dependency has been demonstrated using cell lines and mouse models. The utility of restoring apoptosis in cancer cells through inhibition of pro-survival BCL-2 proteins has been realized in the clinic, where the first specific inhibitor of BCL-2 is approved for use in leukemia. A variety of MCL-1 inhibitors are now undergoing clinical trials for blood cancer treatment and application of this new class of drugs is also being tested in solid cancers. On-target compounds specific to MCL-1 have demonstrated promising efficacy in preclinical models of breast cancer and show potential to enhance the anti-tumor effect of conventional therapies. Taken together, this makes MCL-1 an extremely attractive target for clinical evaluation in the context of breast cancer.Abbreviations: ADC (antibody-drug conjugate); AML (Acute myeloid leukemia); APAF1 (apoptotic protease activating factor 1); bCAFs (breast cancer associated fibroblasts); BCL-2 (B-cell lymphoma 2); BH (BCL-2 homology); CLL (chronic lymphocytic leukemia); EGF (epidermal growth factor); EMT (epithelial to mesenchymal transition); ER (estrogen receptor); FDA (food and drug administration); GEMM (genetically engineered mouse model); HER2 (human epidermal growth factor 2); IL6 (interleukin 6); IMM (inner mitochondrial membrane); IMS (intermembrane space); MCL-1 (myeloid cell leukemia-1); MOMP (mitochondrial outer membrane permeabilisation); MM (multiple myeloma); PDX (patient-derived xenograft); OMM (outer mitochondrial membrane); PROTAC (proteolysis-targeting chimeras) TNBC (triple negative breast cancer); UPS (ubiquitin mediated proteolysis system).


Effect Of Intra Vitreal Injection Of Bevacizumab On Intra-Ocular Pressure.
Bevacizumab has been in use as a therapeutic agent for macular oedema for several years. While its efficacy has been well documented, its use has been shown to cause a transient rise in the intra-ocular pressure. The aim of this study was to evaluate the long term effect of intravitreal injection of Bevacizumab on Intra-ocular pressure. One hundred eyes (n=100) of one hundred patients, requiring intra-vitreal injection of Bevacizumab for diabetic macular oedema were recruited from Shifa Foundation Community Health Centre (SFCHC) between January and December 2014. Patients of glaucoma, ocular hyper-tension, known allergy to Bevacizumab or had injections of Bevacizumab prior to the study were excluded. Intra-ocular pressure was measured using a Goldmann applanation tonometer, prior to, and at six and twelve months after the injection. The pre- and post- injection Intra-ocular pressure was entered into the database. Test of significance was applied to investigate whether there was a significant change in intra-ocular pressure after the injection. The mean age of the patient was 56.97 years (±14.97). The mean intra-ocular pressure was 13.86 (±3.16) mmHg before injection, while postinjection mean Intra-Ocular pressure was 14.21 (±3.12) mmHg and 13.79 (±3.07) at six and twelve months respectively. Between baseline and six months there was a statistically significant difference in intra-ocular pressure (p=0.03), while no significant difference existed in the intraocular pressure between baseline and twelve months (p=0.92). Intra-vitreal injection of Bevacizumab is associated with a statically significant rise in intra-ocular pressure at six months, while no significant difference was seen at twelve months compared to baseline.


Glycosylated hemoglobin in insulin-dependent diabetes mellitus related to preeclampsia.
Preeclampsia may occur due to failure of the second wave of trophoblastic invasion between 16 to 20 weeks of gestation. We studied whether the mean value of glycosylated hemoglobin (HbA1c) during this gestational period was associated with an increased incidence of preeclampsia in insulin-dependent diabetes mellitus. We conducted a retrospective study of 131 insulin-dependent diabetes mellitus (IDDM) pregnancies with HbA1c values available in medical records over the past 10 years. The correlation between high mean HbA1c (>8%) before or after 20 weeks and the incidence of preeclampsia was determined. Mean HbA1c values before 20 weeks were further divided into 10- to 15- and 16- to 20-week intervals. Mean values of HbA1c in these different gestational periods were analyzed by chi(2) or Fisher's exact tests. P < 0.05 was considered statistically significant. We found that IDDM pregnant women with high mean values of HbA1c (>8%) had a significantly higher rate of preeclampsia than those with normal mean values (45 vs. 24%, p = 0.018). However, we found that IDDM pregnant women with an elevated mean HbA1c value at 16-20 weeks', but not 10-15 weeks' or after 20 weeks', gestation had a significantly higher incidence of preeclampsia than those with normal mean HbA1c value (chi(2) = 4.49, p = 0.03). We conclude that a significant association between elevated mean HbA1c values at 16-20 weeks' gestation and a high frequency of preeclampsia in IDDM pregnancies suggests that glycosylated hemoglobin may play an important role in the pathogenesis of preeclampsia in IDDM pregnant women.


Experimental Brucella ovis infection in mouflon (Ovis musimon).
Brucella ovis was isolated for the first time in Italy in 1994 from the genital organs of two domestic rams. In subsequent years bacteriologic and serologic investigations demonstrated an increasing distribution of this disease in domestic sheep. Mouflon (Ovis musimon) occur in several hilly and mountainous areas of Italy where they can potentially contact domestic sheep. To determine if this species may have a role in the epidemiology of B. ovis, four male and four female mouflon, serologically negative for B. ovis and other Brucella spp., were infected intra-conjunctivally with B. ovis strain BG1/94. Physical examinations, including collection of blood samples for serology and bacteriology, were performed weekly. The animals were euthanized 8 mo postinoculation (p.i.). Samples of retropharyngeal, parotid, and iliac lymph nodes; bone marrow; kidneys; spleen; epididymis; testicle; bulbourethral glands; seminal vesicles; uterus; and oviducts were collected from each animal as appropriate for histopathology and bacteriology. At the time of euthanasia none of the animals exhibited obvious clinical signs of brucellosis. The animals seroconverted 2 wk p.i. and became seronegative 24 wk p.i. Bacterial cultures, including hemocultures, were negative. No lesions due to B. ovis infection were revealed by histologic examinations. Brucella ovis probably did not infect mouflon and this wild sheep is not likely to play a role in the epidemiology of contagious epididymitis caused by B. ovis.


Effective and complex stimulation of the biodegradation system of fungus Cerrena unicolor by rapeseed meal fermentation.
The effect of supplementation of medium with rapeseed meal (RM) on production of biotechnologically important enzymes was investigated in submerged cultures of the white rot fungus Cerrena unicolor. The addition of RM (3.5% w/v) distinctly stimulated the activities of laccase, chitinase, and β-glucosidase. As compared to the control, the activities of chitinase, β-glucosidase, and laccase in the RM supplemented cultures were up to 4.1, 8.4, and 3.9 times higher, respectively. The results of the spectrophotometric and spectrofluorometric measurements were additionally confirmed by zymographic analysis of the samples. The level of sugars and phenolic compounds as well as the antioxidative ability of fungal preparations were also determined. The results obtained indicate that the submerged liquid fermentation of rapeseed meal can be proposed as an inexpensive and very effective method for biotechnological production of chitinase, β-glucosidase, and laccase by C. unicolor.


Prevalence of ECG findings in very old people.
The electrocardiograms of 559 persons, 83% of the total population 85 years of age or over in the city of Tampere, were evaluated according to the classification of the modified Minnesota code. Electrocardiograms showed no codable item in only 3.6% of the subjects. The prevalence of the most frequent electrocardiographic findings was: T wave inversion 53.3%, counter-clockwise rotation 42.9%, ST junction depression 42.8%, premature beats 33.8%, Q-QS pattern 21.3% and atrial fibrillation 17.4%. The prevalence of left axis deviation, left anterior hemiblock and right bundle branch block was statistically significantly higher in men than in women. Electrocardiographic abnormalities suggestive of ischaemic heart disease were present in 45.3% with no statistically significant relation to sex or age. The results are discussed and compared with those of electrocardiographic studies concerning age groups over 80 and 90 years.


The pretransplant Follicular Lymphoma International Prognostic Index is associated with survival of follicular lymphoma patients undergoing autologous hematopoietic stem cell transplantation.
We retrospectively evaluated the association of the Follicular Lymphoma International Prognostic Index (FLIPI) and other characteristics with survival following high-dose therapy and autologous stem cell transplantation (ASCT) in 207 consecutive follicular lymphoma (FL) patients. The FLIPI was associated with OS both when evaluated as a categorical variable (0 - 1 vs. 2 vs. 3 vs. 4, p = 0.01, global test) and a continuous linear variable (p = 0.002). The association of FLIPI with survival appeared to be more relevant for patients who received standard conditioning regimens compared to those that were treated with high-dose radioimmunotherapy (p = 0.004). Among all patients, mortality was also associated with chemosensitive disease (HR = 0.47, p = 0.01) or untreated relapse (HR = 0.20, p = 0.0002) vs. chemoresistant disease, and > or =2 extranodal sites (HR = 2.82, p = 0.03) after adjusting for FLIPI. These data suggest that the FLIPI and select non-FLIPI factors after adjustment for the FLIPI are associated with survival in FL patients undergoing ASCT.


Resveratrol activates SIRT1 in a Lamin A-dependent manner.
Human sirtuin1 (SIRT1), the closest homolog of the yeast sir2 protein, functions as an NAD+-dependent histone and non-histone protein deacetylase in several cellular processes, like energy metabolism, stress responses, aging, etc. In our recent study, we have shown that lamin A (a major nuclear matrix protein) directly binds with and activates SIRT1. Resveratrol, a natural phenol, has long been known as an activator of SIRT1. However, resveratrol's direct activation of SIRT1 has been refuted several times. In our study, we have provided a mechanistic explanation to this question, and have shown that resveratrol activates SIRT1 by increasing its binding with lamin A, thus aiding in the nuclear matrix (NM) localization of SIRT1. We have also shown that rescue of adult stem cell (ASC) decline in laminopathy-based premature aging mice by resveratrol is SIRT1-dependent. Further, resveratrol's ameliorating effects on progeria and its capacity to extend lifespan in progeria mice has been established. Here we have summarized these findings and their probable implications on other aspects, like chromatin remodeling, stem cell therapy, DNA damage responses, etc.


Managing a Heterogeneous Cluster.
Most HPC clusters are purchased with a large quantity of identical hardware, which is maintained through its lifecycle and then another HPC cluster takes its place. However, some clusters, like ours, are maintained by frequently adding new hardware, which is then integrated into the system. Over the years, the cluster has grown to include 300+ compute nodes with 8000+ cores from 6 vendors, spanning 5 generations of CPUs; 7 network technologies from 6 switch vendors (1Gbps-100Gbps, including Ethernet, Infiniband, and OmniPath); 102 GPUs (3 different GPU models); 28 storage nodes (3+ PB raw storage); and 7 virtualization nodes hosting 65 VMs. Having such a diverse system has significant advantages, although the management is more difficult. This paper outlines our strategy of managing this very heterogeneous and complex system. Topics covered include software optimization, consistency of operating system updates, identity management, resource prioritization, network infrastructure, storage, and management of non-compute-intensive resources. Our combination of open source and internally developed software used to manage this cluster are a model to other heterogeneous systems and to smaller clusters which have not expanded because of management worries.


Morphological Effects of Au Nanoparticles on Electrochemical Sensing Platforms for Nitrite Detection.
Au nanoparticles were synthesized in a soft template of pseudo-polyanions composed of polyvinylpyrrolidone (PVP) and sodium dodecyl sulfate (SDS) by the in situ reduction of chloroauric acid (HAuCl4) with PVP. The particle sizes and morphologies of the Au nanoparticles were regulated with concentrations of PVP or SDS at room temperature. Distinguished from the Au nanoparticles with various shapes, Au nanoflowers (AuNFs) with rich protrusion on the surface were obtained at the low final concentration of SDS and PVP. The typical AuNF synthesized in the PVP (50 g·L-1)-SDS (5 mmol·L-1)-HAuCl4 (0.25 mmol·L-1) solution exhibited a face-centered cubic structure dominated by a {111} crystal plane with an average equivalent particle size of 197 nm and an average protrusion height of 19 nm. Au nanoparticles with four different shapes, nanodendritic, nanoflower, 2D nanoflower, and nanoplate, were synthesized and used to modify the bare glassy carbon electrode (GCE) to obtain Au/GCEs, which were assigned as AuND/GCE, AuNF/GCE, 2D-AuNF/GCE, and AuNP/GCE, respectively. Electrochemical sensing platforms for nitrite detection were constructed by these Au/GCEs, which presented different detection sensitivity for nitrites. The results of cyclic voltammetry (CV) demonstrated that the AuNF/GCE exhibited the best detection sensitivity for nitrites, and the surface area of the AuNF/GCE was 1.838 times of the bare GCE, providing a linear c(NO2-) detection range of 0.01-5.00 µmol·L-1 with a limit of detection of 0.01 µmol·L-1. In addition, the AuNF/GCE exhibited good reproducibility, stability, and high anti-interference, providing potential for application in electrochemical sensing platforms.


Agonist-induced desensitization, internalization, and phosphorylation of the sst2A somatostatin receptor.
Cellular responsiveness to the inhibitory peptide somatostatin (SRIF) or its clinically used analogs can desensitize with agonist exposure. While desensitization of other seven-transmembrane domain receptors is mediated by receptor phosphorylation and/or internalization, the mechanisms mediating SRIF receptor (sst) desensitization are unknown. Therefore, we investigated the susceptibility of the sst2A receptor isotype to ligand-induced desensitization, internalization, and phosphorylation in GH-R2 cells, a clone of pituitary tumor cells overexpressing this receptor. A 30-min exposure of cells to either SRIF or the analog SMS 201-995 (SMS) reduced both the potency and efficacy of agonist inhibition of adenylyl cyclase. Internalization of receptor-bound ligand was rapid (t1/2 = 4 min) and temperature-dependent. SRIF and SMS increased the phosphorylation of the 71-kDa sst2A protein 25-fold within 15 min. Receptor phosphorylation was dependent on both the concentration and time of agonist exposure and was not affected by pertussis toxin pretreatment, indicating that receptor occupancy rather than second messenger formation was required. Receptor phosphorylation was also stimulated by phorbol 12-myristate 13-acetate activation of protein kinase C. Both ligand-stimulated and phorbol 12-myristate 13-acetate-stimulated receptor phosphorylation occurred primarily on serine. These studies are the first demonstration of agonist-dependent desensitization, internalization, and phosphorylation of the sst2A receptor and suggest that phosphorylation may mediate the homologous and heterologous regulation of this receptor.


Efficiency improvement in InGaN-based solar cells by indium tin oxide nano dots covered with ITO films.
InGaN based MQW solar cells have been fabricated with 4 different transparent top electrode structures: (1)- ITO 200 nm, (2)-ITO nano dots only, (3)-ITO nano dots on ITO 50 nm and (4)-ITO nano dots on ITO 100 nm. The solar cell with the ITO 50 nm on ITO nano dots under AM 1.5 conditions showed the best results: 2.3 V for V(oc), 0.69 mA/cm(2) for J(sc), 41.8% for peak EQE, and 0.91% for conversion efficiency. Efficiency improvement was possible due to the decreased reflectance achieved by the ITO nano dots covered with an ITO film with optimized thickness.


Tumor necrosis factor α modulates sodium-activated potassium channel SLICK in rat dorsal horn neurons via p38 MAPK activation pathway.
The dorsal horn (DH) of the spinal cord is the integrative center that processes and transmits pain sensation. Abnormal changes in ion channel expression can enhance the excitability of pain-related DH neurons. Sodium-activated potassium (KNa) channels are highly expressed particularly in the central nervous system; however, information about whether rat DH neurons express the SLICK channel protein is lacking, and the direct effects on SLICK in response to inflammation and the potential signaling pathway mediating such effects are yet to be elucidated. Here, using cultured DH neurons, we have shown that tumor necrosis factor-α inhibits the total outward potassium current IK and the KNa current predominantly as well as induces a progressive loss of firing accommodation. However, we found that this change in channel activity is offset by the p38 inhibitor SB202190, thereby suggesting the modulation of SLICK channel activity via the p38 MAPK pathway. Furthermore, we have demonstrated that the tumor necrosis factor-α modulation of KNa channels does not occur at the level of SLICK channel gating but arises from possible posttranslational modification.


Understanding the nature of medication errors in an ICU with a computerized physician order entry system.
We investigated incidence rates to understand the nature of medication errors potentially introduced by utilizing a computerized physician order entry (CPOE) system in the three clinical phases of the medication process: prescription, administration, and documentation. Overt observations and chart reviews were employed at two surgical intensive care units of a 950-bed tertiary teaching hospital. Ten categories of high-risk drugs prescribed over a four-month period were noted and reviewed. Error definition and classifications were adapted from previous studies for use in the present research. Incidences of medication errors in the three phases of the medication process were analyzed. In addition, nurses' responses to prescription errors were also assessed. Of the 534 prescriptions issued, 286 (53.6%) included at least one error. The proportion of errors was 19.0% (58) of the 306 drug administrations, of which two-thirds were verbal orders classified as errors due to incorrectly entered prescriptions. Documentation errors occurred in 205 (82.7%) of 248 correctly performed administrations. When tracking incorrectly entered prescriptions, 93% of the errors were intercepted by nurses, but two-thirds of them were recorded as prescribed rather than administered. The number of errors occurring at each phase of the medication process was relatively high, despite long experience with a CPOE system. The main causes of administration errors and documentation errors were prescription errors and verbal order processes. To reduce these errors, hospital-level and unit-level efforts toward a better system are needed.


Effects of crystalline anisotropy on resonant acoustic loss of torsional quartz viscometers.
Vibrational modes of unrestrained elastic cylinders of trigonal crystals are studied using Ritz-based polynomial approximations for displacements formulated in rectangular Cartesian coordinates. The selected orientation of the threefold trigonal axis is perpendicular to the cylinder axis, corresponding to the configuration employed in torsional quartz viscometry (TQV) for characterizing Newtonian fluids. A revised working equation for TQV is derived, incorporating effects of crystalline anisotropy, and Ritz results are used to numerically quantify effects of acoustic radiation from surface-normal displacements and viscous loss from nontorsional surface-parallel displacements of resonant modes corresponding to the purely torsional modes of isotropic cylinders traditionally employed as an approximation in TQV analysis. For a cylinder typical of TQV, with 3 mm diameter and 50 mm length, the anisotropy-related correction to the extracted fluid viscosity is a positive shift of 36 ppm relative to the isotropic approximation, if radiative losses are neglected. This contribution is independent of fluid properties. Radiative losses depend on the properties of the fluid and reduce the extracted viscosity. The total magnitude of corrections varies between several tens of parts per million for low density gases to values on the order of 0.01% for normal liquids near atmospheric pressure and 0.06% for superfluid helium.


Reactions of B atoms and clusters with NO: experimental and theoretical characterization of novel molecules containing B, N, and O.
Reactions of boron atoms and clusters with NO molecules in solid argon have been studied using matrix isolation infrared absorption spectroscopy. The reaction products were identified by isotopic substitution ((10)B, (11)B, (15)N(16)O, (14)N(18)O, and mixtures) and comparison with density functional calculations of isotopic frequencies. In solid argon, boron atoms spontaneously reacted with NO to form the insertion molecule NBO. The BNBO and OBNNO molecules were formed by the B and NO addition reactions to NBO. The linear BBNO and BBBNO nitrosyls also were formed spontaneously on annealing. These molecules photochemically rearranged to the more stable BNBO and BNBBO isomers, which have linear polyyne-like structures. The photosensitive OBNNO molecule decomposed to form the NNBO(2) van der Waals complex. In addition, the novel OBON diradical was also formed on photolysis in high-concentration NO experiments.


Ablative procedures in patients with metastatic breast carcinoma.
The ability to determine the content of sex steroid receptors in breast carcinoma cells has markedly enhanced the clinician's ability to predict the response to hormonal therapy in patients with metastatic breast carcinoma. Formerly the surgical ablation of endocrine organs (hypophysectomy, adrenalectomy, and oophorectomy) was used as the initial therapy in many patients with metastatic breast carcinoma. Currently, however, only oophorectomy is employed as the initial treatment of choice in patients with recurrent breast carcinoma, and its use is exclusively limited to premenopausal or perimenopausal patients whose tumors are estrogen-receptor positive. The decreased utilization of surgical ablative procedures is primarily due to the introduction into clinical practice of two pharmacologic agents, the antiestrogen, tamoxifen, and the adrenal blocking agent, aminoglutethimide. When administered to postmenopausal patients with metastatic breast carcinoma, these pharmacologic agents induce remissions as frequently as do surgical ablative procedures; however, their use is associated with distinctly less morbidity and virtually no mortality.


Is nitric oxide a key target in the pathogenesis of brain lesions during the development of Alzheimer's disease?
Nitric oxide (NO) is a short-life key bioregulatory active molecule in the cardiovascular, immune and nervous systems. NO is synthesized by converting L-arginine to L-citrulline by enzymes called NO synthase (NOS). The growing body of evidence strongly supports the theory that this molecule appears to be one of the key targets for the disruption of normal brain homeostasis, which causes the development of brain lesions and pathology such as in Alzheimer's disease (AD) or other related dementia. The vascular content of NO activity appears especially to be a main contributor to this pathology before the over-expression of other NOS isoforms activity in a different brain cellular compartment. We speculate that pharmacological intervention using NO donors and/or NO suppressors will be able to delay or minimize the development of brain pathology and further progression of mental retardation.


Haemophilia patients' unmet needs and their expectations of the new extended half-life factor concentrates.
National Member Organisations (NMO) of persons with haemophilia (PWH) from the DACH Region (D = Germany, A = Austria, CH = Switzerland) were interested to better understand PWH's expectations and concerns of extended half-life (EHL) factor concentrates (FC) before availability in these countries. Based on an expert meeting and focus groups conducted across Germany a survey for haemophilia patients and their parents was developed and was sent out to 2,644 PWH. One thousand and seven questionnaires were sent back (38.1%); 743 adults and 262 parents. Most patients had haemophilia A (84.5%), were severely affected (73.7%), received prophylaxis (57%) and used recombinant FC (60.2%). One-quarter did not know the correct half-life of their FC [HA/FVIII: 26%, HB/FIX: 31.1%]. Four percent were unsatisfied with their current FC, mainly with short half-life of FC and difficult manageability. They expected from new EHL products less frequent injections (55.2%), better efficacy (32.1%) and safety/no side effects (15.7%); 59.5% would be willing to switch to new products if they have a prolonged half-life and the same safety of the current FC. They wish more information about half-life (84.4%), possible side-effects (81.3%) and efficacy (77%) and wanted to receive information about new products from their haemophilia treater (76.3%) and the newsletter of their NMO (74.3%). Significant differences across countries were found. The representative survey could show that although PWH were generally satisfied with their current FC, the majority would be willing to switch to EHL products assuming half-life is prolonged and has the same safety of the current FC.


A high-fat diet modulates iron metabolism but does not promote liver fibrosis in hemochromatotic Hjv⁻/⁻ mice.
Hemojuvelin (Hjv) is a membrane protein that controls body iron metabolism by enhancing signaling to hepcidin. Hjv mutations cause juvenile hemochromatosis, a disease of systemic iron overload. Excessive iron accumulation in the liver progressively leads to inflammation and disease, such as fibrosis, cirrhosis, or hepatocellular cancer. Fatty liver (steatosis) may also progress to inflammation (steatohepatitis) and liver disease, and iron is considered as pathogenic cofactor. The aim of this study was to investigate the pathological implications of parenchymal iron overload due to Hjv ablation in the fatty liver. Wild-type (WT) and Hjv(-/-) mice on C57BL/6 background were fed a standard chow, a high-fat diet (HFD), or a HFD supplemented with 2% carbonyl iron (HFD+Fe) for 12 wk. The animals were analyzed for iron and lipid metabolism. As expected, all Hjv(-/-) mice manifested higher serum and hepatic iron and diminished hepcidin levels compared with WT controls. The HFD reduced iron indexes and promoted liver steatosis in both WT and Hjv(-/-) mice. Notably, steatosis was attenuated in Hjv(-/-) mice on the HFD+Fe regimen. Hjv(-/-) animals gained less body weight and exhibited reduced serum glucose and cholesterol levels. Histological and ultrastructural analysis revealed absence of iron-induced inflammation or liver fibrosis despite early signs of liver injury (expression of α-smooth muscle actin). We conclude that parenchymal hepatic iron overload does not suffice to trigger progression of liver steatosis to steatohepatitis or fibrosis in C57BL/6 mice.


Comprehensive competency assessment of malaria microscopists and laboratory diagnostic service capacity in districts stratified for malaria elimination in Ethiopia.
Federal Ministry of Health (FMoH) Ethiopia achieved significant declines in malaria mortality and incidence and has recently launched malaria elimination in selected low transmission settings. Successful malaria elimination calls for rapid and accurate diagnosis of cases so that the patients can promptly be treated before the occurrence of transmission. Therefore, this study assessed the competency of malaria microscopists using panal slides, and laboratory service availability and readiness in terms of supplies and equipments in malaria elimination targeted districts in Ethiopia. A cross-sectional study was conducted from February to June 2018 in all hospitals, health centers and private clinics in 20 malaria elimination targeted districts, selected out of the 6 regional states in Ethiopia. All malaria microscopists available in the study health facilities during the study period were included in the study. Questionnaires were used for interviewing sociodemography of personnel and laboratory supplies. Per World Health Organization (WHO) criteria set for proficiency testing, 10 Giemsa stained malaria slide panels (8 positive low/high density pf/pv/Mixed and 2 negative slides) were administered to each study participant for performance assessment on malaria parasite detection, species identification and parasite count using light microscopy. The slide panels are PCR confirmed and WHO approved ones, which have been stored in the slide banks at the national reference laboratory in Ethiopian Public Health Institute. In this assessment, 17(16%) district hospitals, 71(67%) health centers (HCs) and 18(17%) private clinics (PCs) were included. Of the 18 PCs, only 10(55.6%) had license certificate. Of the study facilities, 91.5%(97) use light microscopy, 2.83%(3) use RDTs and 2.9%(3) use both microscopy and RDT to detect malaria. Accessible and appropriate storage of Giemsa was reported by 58.8%(10) hospitals, 81.7%(58) HCs & 72.2%(13) private clinics. Of the 1896 malaria positive & 474 negative slides administered to 237 study participants, 318(16.8%) slides reported falsely negative & 47(9.9%) reported falsely positive. The participants achieved "good" grade [Agreement(A): 84.6%, Kappa(K): 0.6] on parasite detection and "poor" agreement (A: 43.8%; K: 0.11) on every species identification. No or slight agreement seen on differentiation of P. falciparum from other species (A: 28.41%; K:0.29). Above 95%(201) of participants, did not count or used plus system of parasite estimation which is the least accurate and unreccomended method per WHO guideline. In the current study, low performance of malaria microscopists particularly in species identification & poor to moderate capacity of laboratories observed. This is really a great obstacle to malaria elimination strategy of the country. Therefore, national malaria control and elimination program in collaboration with partners is supposed to provide comprehensive training for professionals giving laboratory service and to fulfill laboratory supplies to have the gold standard service.


[Primary hyperparathyroidism and pregnancy. Aspects of neonatal morbidity].
Primary hyperparathyroidism has to be accused to cause serious morbidity during pregnancy not only on the maternal, but also on the fetal side: the fetus is threatened by prematurity, dystrophy and an increased risk of stillbirth. Postpartually hypocalcaemia and tetany may be observed as the result of neonatal hypoparathyroidism caused by maternal and thus also fetal hypercalcaemia. We report the case of a 32-year-old pregnant woman suffering from a severe form of primary hyperparathyroidism caused by an adenoma of the parathyroidea. The tumor was removed in the 34. week of pregnancy. Six weeks later the patient delivered a healthy boy (birth weight 3450 g). A survey is given of the therapeutical procedures that should be arranged individually by interdisciplinary consulting depending on the degree of maternal disease and on the gestational age.


Declining relative risks for lung cancer after cessation of asbestos exposure.
All studies that provide follow-up information for workers more than 35 years after initial exposure to asbestos show a declining ratio of observed to expected lung cancer deaths at the end of follow-up. The most parsimonious explanation of this finding is that relative risk for lung cancer begins to decline sometime after cessation of asbestos exposure.


Treatment of pulmonary blastomycosis with high-dose liposomal amphotericin B in a patient receiving extracorporeal membrane oxygenation.
Blastomycosis-associated acute respiratory distress syndrome (ARDS) has a rare incidence. We report the case of a 29-year-old man with blastomycosis-associated ARDS receiving extracorporeal membrane oxygenation and managed with high-dose liposomal amphotericin B. This case illustrates the importance of timely diagnosis of pulmonary blastomycosis and appropriate dosing of antifungal therapy.


Interleukin-1 beta induces tumor necrosis and early morphologic and metabolic changes in transplantable mouse tumors. Similarities with the anti-tumor effects of tumor necrosis factor alpha or beta.
Peri-tumoral injection of recombinant human interleukin-1 beta in mice transplanted s.c. with Friend erythroleukemia cells (FLC) resulted in marked inhibition of tumor growth and increased survival. However, in vitro treatment of FLC (745 or 3Cl-8) with IL-1 beta barely inhibited cell multiplication. IL-1 beta, injected into established solid tumors, induced marked morphologic changes. Vascular congestion and focal extravasation of erythrocytes were observed as early as 6 hr after injection with IL-1 beta of FLC and L1210 tumors and HeJ16 fibrosarcomas. Focal areas of disaggregation of tumor cells and tumor necrosis were observed 6 and 24 hr after IL-1 injection. These morphologic changes were similar to those observed in FLC tumors or HeJ16 fibrosarcomas treated with TNF-alpha or beta. These cytokines determined morphological changes in tumor blood vessels of FLC tumors within 1 hr of injection. Freshly dissected FLC tumors and their tissue extracts were studied by Nuclear Magnetic Resonance (NMR) spectroscopy, shortly after peri-tumoral injection of IL-1 beta or TNF-beta. After 6 hr, both cytokines induced a 3-fold reduction in the levels of two catabolites, glycerophosphorylcholine and glycerophosphorylethanolamine, an accumulation of sn-glycerol 3-phosphate and a more than 10-fold increase in the choline/phosphorylcholine ratio. These results are similar to those reported for TNF-alpha, and can be interpreted on the basis of an activation of glycerophosphorylcholine phosphodiesterase (EC 18.104.22.168) and partial inhibition of choline kinase (EC 22.214.171.124). IL-1 beta and TNF-beta (like TNF-alpha) also induced alkaline shifts (0.10-0.25 units) in the average intratumoral pH value. We suggest that alterations of tumor blood vessels may be the primary events in solid tumors treated with IL-1 beta or TNF. Such alterations lead to early changes in tumor metabolism and subsequent tumor cell degeneration.


The identification of a novel C27 diene, cholesta-5,8-dien-3 beta-OL, in tissues of rats given AY-9944 (trans-1,4-bis(2-dichlorobenzylaminoethyl)cyclohexane) in pregnancy.
Treatment of pregnant rats with AY-9944, a drug interfering with the last steps of cholesterol biosynthesis, accumulated cholesterol precursors in brain and liver of newborn animals. Different sterol profiles were found in these organs. Along with cholesterol and cholesta-5,7-dien-3 beta-ol, present in both tissues, liver was found to contain a hitherto unreported sterol, absent in brain. The structure of cholesta-5,8-dien-3 beta-ol was attributed to this compound by mass spectrometric, 1H, and 13C NMR analysis.