Use of Doxycycline in a Patient following Minocycline-Induced Lupus.
Minocycline, a tetracycline antibiotic, is commonly used to treat rosacea and acne vulgaris. A rare adverse reaction of minocycline use is the development of drug-induced lupus. Fortunately, most patients recover from minocycline-induced lupus (MIL) after the drug is discontinued. However, many patients, after recovering from MIL, may desire further treatment for their acne and may consider doxycycline, a close relative of minocycline. Though no cases of doxycycline-induced lupus have been reported, there is little guidance in the medical literature as to whether doxycycline poses a particular risk to patients who have recovered from MIL. We report the long-term follow-up of a patient who recovered from MIL (the diagnosis satisfying clinical and laboratory criteria) and was treated for 8 years with various forms of doxycycline without any untoward effects, suggesting that, at least in some cases, doxycycline can be used safely following MIL.


Comparison of the 2MACE and TIMI-AF Scores for Composite Clinical Outcomes in Anticoagulated Atrial Fibrillation Patients.
Two risk scores have been developed to predict composite outcomes in atrial fibrillation (AF): the 2MACE and TIMI-AF scores. The aim of this study was to compare the predictive ability of these scores in 2 separate warfarin-treated cohorts (one 'real world', one clinical trial) of AF patients.Methods and Results:The 2MACE and TIMI-AF scores were calculated in the 'real-world' ATHERO-AF cohort (n=907), and in the randomized controlled AMADEUS trial (n=2,265). Endpoints were major adverse cardiovascular events (MACEs), net clinical outcomes (NCO) and a combination of them, namely "clinically relevant events" (CREs). ROC curves showed similar predictive ability for MACE for 2MACE and TIMI-AF, in both the ATHERO-AF (0.698 vs. 0.688, respectively P=0.783) and AMADEUS (0.657 vs. 0.569, respectively P=0.057) cohorts. Similarly, the TIMI-AF showed a comparable c-index with 2MACE for NCOs in the ATHERO-AF (0.676 vs. 0.667, P=0.737), and AMADEUS (0.666 vs. 0.663, P=0.859) cohorts. No differences were found between the 2 scores for the prediction of CREs (0.675 vs. 0.684, P=0.740 in ATHERO-AF and 0.669 vs. 0.667, P=0.889 in AMADEUS for 2MACE and TIMI-AF, respectively). This study showed that the 2MACE and TIMI-AF scores had modest but significant predictive ability for composite outcomes in AF. The clinical usefulness of both scores was similar, but the 2MACE score may be simpler and easy to use.


[A CASE OF MILIARY TUBERCULOSIS ORIGINATED FROM CUTANEOUS INFECTION].
An 86-year-old woman with severe dementia had been treated with oral prednisolone at 2 mg/day for autoimmune bullous dermatosis for several years. One year ago, she referred to our hospital due to an ulcerative skin lesion over the right tibial tuberosity. The lesion was treated by an iodine-containing ointment, but did not heal. Subsequently, a new skin lesion appeared in the right popliteal fossa. One month ago, the patient had increased sputum production that was accompanied by fever, anorexia, and dyspnea; consequently, she visited our department. Chest computed tomography revealed diffuse micronodules with ground-glass attenuation. Acid-fast bacteria staining of the sputum was positive and the polymerase chain reaction detected Mycobacterium tuberculosis. In addition, the bacilli were also found in the skin lesions of the right limb. Therefore, a diagnosis of cutaneous, and miliary tuberculosis was made. Although the anti-tuberculous combination chemotherapy consisting of isoniazid, rifampicin, and ethambutol was immediately initiated, her condition did not improve. She died on day 19 of hospitalization. Drug susceptibility testing revealed no resistance to all the three drugs; hence, it was concluded that the time-delay in diagnosis of cutaneous tuberculosis lead to the progression to miliary tuberculosis and subsequent death.


Mechanisms and controversies in mutant Cul3-mediated familial hyperkalemic hypertension.
Autosomal dominant mutations in cullin-3 ( Cul3) cause the most severe form of familial hyperkalemic hypertension (FHHt). Cul3 mutations cause skipping of exon 9, which results in an internal deletion of 57 amino acids from the CUL3 protein (CUL3-∆9). The precise mechanism by which this altered form of CUL3 causes FHHt is controversial. CUL3 is a member of the cullin-RING ubiquitin ligase family that mediates ubiquitination and thus degradation of cellular proteins, including with-no-lysine [K] kinases (WNKs). In CUL3-∆9-mediated FHHt, proteasomal degradation of WNKs is abrogated, leading to overactivation of the WNK targets sterile 20/SPS-1 related proline/alanine-rich kinase and oxidative stress-response kinase-1, which directly phosphorylate and activate the thiazide-sensitive Na+-Cl- cotransporter. Several groups have suggested different mechanisms by which CUL3-∆9 causes FHHt. The majority of these are derived from in vitro data, but recently the Kurz group (Schumacher FR, Siew K, Zhang J, Johnson C, Wood N, Cleary SE, Al Maskari RS, Ferryman JT, Hardege I, Figg NL, Enchev R, Knebel A, O'Shaughnessy KM, Kurz T. EMBO Mol Med 7: 1285-1306, 2015) described the first mouse model of CUL3-∆9-mediated FHHt. Analysis of this model suggested that CUL3-∆9 is degraded in vivo, and thus Cul3 mutations cause FHHt by inducing haploinsufficiency. We recently directly tested this model but found that other dominant effects of CUL3-∆9 must contribute to the development of FHHt. In this review, we focus on our current knowledge of CUL3-∆9 action gained from in vitro and in vivo models that may help unravel this complex problem.


Suppressor analysis of eepR mutant defects reveals coordinate regulation of secondary metabolites and serralysin biosynthesis by EepR and HexS.
The EepR transcription factor positively regulates secondary metabolites and tissue-damaging metalloproteases. To gain insight into mechanisms by which EepR regulates pigment and co-regulated factors, genetic suppressor analysis was performed. Suppressor mutations that restored pigment to the non-pigmented ∆eepR mutant mapped to the hexS ORF. Mutation of hexS also restored haemolysis, swarming motility and protease production to the eepR mutant. HexS is a known direct and negative regulator of secondary metabolites in Serratia marcescens and is a LysR family regulator and an orthologue of LrhA. Here, we demonstrate that HexS directly controls eepR and the serralysin gene prtS. EepR was shown to directly regulate eepR expression but indirectly regulate hexS expression. Together, these data indicate that EepR and HexS oppose each other in controlling stationary phase-associated molecules and enzymes.


[Effectiveness and safety of conversion therapy with the combination of sirolimus with low dose cyclosporine in renal transplantation recipients: a five-year clinical observation].
To assess the effectiveness and safety of the conversion therapy from traditional cyclosporine (CsA) triple immunosuppression therapy to sirolimus (SRL) combined with low dose CsA and prednisone (Pred) in renal transplantation recipients in a five-year follow-up period. A prospective, open-label non-randomized study was performed with 46 renal allograft recipients who visited Tongji Hospital regularly for follow-up visits between January 2007 and May 2011 and were taking CsA+ mycophenolate mofetil (MMF)+ Pred. Conversion therapy to SRL+ low dose CsA+ Pred was initiated after renal transplantation. The recipients were allocated to 2 groups according to their renal function and proteinuria before the conversion: active conversion group [n=27, serum creatinine (SCr) ≤ 140 μmol/L with no or minimal proteinuria] and passive conversion group [n=19, SCr>140 μmol/L with less than moderate proteinuria]. After conversion, dosages of SRL and CsA were adjusted for trough levels of 5-7 μg/L and 20-60 μg/L, respectively. SCr and urine protein were compared before and after the conversion in five-year follow-up. Incidence of acute rejection, renal graft survival and SRL-related adverse effects of the immunosuppressive regimen were also observed. After conversion, an average 63% dose reduction of CsA was achieved in all the patients. In the active conversion group, the mean SCr level was (110±19) μmol/L at the time of conversion. Eight patients in this group withdrew from the study during the follow-up period for the following reasons: arthralgia (1 case), deteriorated proteinuria (2 cases), chronic diarrhea (2 cases), mild or suspicious acute rejection (2 cases), and recurrent fever (1 case). The rest patients (19/27) with a mean follow-up time of 5 years had a stable SCr level [(103±12) μmol/L] and a 100% 5-year graft survival. In the passive conversion group, the mean SCr level was (205±45) μmol/L at the time of conversion. There were 4 patients quitting the study, 2 for deteriorated proteinuria and 2 for lost to follow-up. Chronic allograft failure developed in 10 patients in this group 1-50 months after conversion, while the remaining 5 patients had a stable SCr during the 5-year follow-up period [(218 ±46) μmol/L before conversion vs (205±73) μmol/L 5 years after conversion]. The overall 5-year graft survival after the conversion therapy in the passive conversion group was 33.3%, significantly lower than that of the active conversion group (P<0.001). Acute rejection was observed in 2 cases in the active conversion group, while not observed in the passive conversion group. None of the patients developed leukopenia, thrombocytopenia, oral ulcer, or pneumonia in the follow-up. The combination therapy of SRL and low dose of CsA is overall a safe and effective maintenance immunosuppressive regimen, but it is important to initiate at an appropriate stage. More favourable long-term benefits may be obtained from the conversion therapy in patients with normal or only slightly impaired renal graft function. It may offer an option of individualized immunosuppressive therapy after renal transplantation.


Stochastic basins of attraction for metastable states.
Basin of attraction of a stable equilibrium point is an effective concept for stability analysis in deterministic systems; however, it does not contain information on the external perturbations that may affect it. Here we introduce the concept of stochastic basin of attraction (SBA) by incorporating a suitable probabilistic notion of basin. We define criteria for the size of the SBA based on the escape probability, which is one of the deterministic quantities that carry dynamical information and can be used to quantify dynamical behavior of the corresponding stochastic basin of attraction. SBA is an efficient tool to describe the metastable phenomena complementing the known exit time, escape probability, or relaxation time. Moreover, the geometric structure of SBA gives additional insight into the system's dynamical behavior, which is important for theoretical and practical reasons. This concept can be used not only in models with small noise intensity but also with noise whose amplitude is proportional or in general is a function of an order parameter. As an application of our main results, we analyze a three potential well system perturbed by two types of noise: Brownian motion and non-Gaussian α-stable Lévy motion. Our main conclusions are that the thermal fluctuations stabilize the metastable system with an asymmetric three-well potential but have the opposite effect for a symmetric one. For Lévy noise with larger jumps and lower jump frequencies ( α=0.5) metastability is enhanced for both symmetric and asymmetric potentials.


Electrochemical Investigation of Arsenic Redox Processes on Pyrite.
The specific Eh-pH conditions and mechanism(s) for the reduction of arsenite, As(III), by pyrite are incompletely understood. A fundamental question is what role the pyrite surface plays in the reduction process. We used electrochemical methods to evaluate the reduction of As(III) under controlled redox conditions. As(III) reduction to elemental As(0) occurs on the pyrite surface under suboxic-reducing conditions and is promoted at low pH. Remarkably, As(III) reduction on pyrite occurs at similar potentials to those for reduction on platinum metal, suggesting a similar mechanism and kinetics for these surfaces. The onset for As(III) reduction at pH ≤ 3.5 coincides with the potential for hydrogen electroadsorption on pyrite, E ≈ +0.1 V (versus RHE). Batch reactions show that As(III) is reduced on pyrite at the Eh-pH predicted by the electrochemical study. X-ray photoelectron spectroscopy reveals that, at pH ≤ 3.5, a significant fraction of the surface arsenic (30-60%) has an oxidation state consistent with As(0). Here, we propose a mechanism whereby atomic hydrogen that forms on ferric (hydr)oxide surface layers promotes As(III) reduction at low Eh and pH. Insights provided by this study will have implications for understanding the controls on dissolved As(III) concentrations in suboxic-anoxic environments.


Lithographically patterned electrodeposition of gold, silver, and nickel nanoring arrays with widely tunable near-infrared plasmonic resonances.
A novel low-cost nanoring array fabrication method that combines the process of lithographically patterned nanoscale electrodeposition (LPNE) with colloidal lithography is described. Nanoring array fabrication was accomplished in three steps: (i) a thin (70 nm) sacrificial nickel or silver film was first vapor-deposited onto a plasma-etched packed colloidal monolayer; (ii) the polymer colloids were removed from the surface, a thin film of positive photoresist was applied, and a backside exposure of the photoresist was used to create a nanohole electrode array; (iii) this array of nanoscale cylindrical electrodes was then used for the electrodeposition of gold, silver, or nickel nanorings. Removal of the photoresist and sacrificial metal film yielded a nanoring array in which all of the nanoring dimensions were set independently: the inter-ring spacing was fixed by the colloidal radius, the radius of the nanorings was controlled by the plasma etching process, and the width of the nanorings was controlled by the electrodeposition process. A combination of scanning electron microscopy (SEM) measurements and Fourier transform near-infrared (FT-NIR) absorption spectroscopy were used to characterize the nanoring arrays. Nanoring arrays with radii from 200 to 400 nm exhibited a single strong NIR plasmonic resonance with an absorption maximum wavelength that varied linearly from 1.25 to 3.33 μm as predicted by a simple standing wave model linear antenna theory. This simple yet versatile nanoring array fabrication method was also used to electrodeposit concentric double gold nanoring arrays that exhibited multiple NIR plasmonic resonances.


Selective ion monitoring of quinochalcone C-glycoside markers for the simultaneous identification of Carthamus tinctorius L. in eleven Chinese patent medicines by UHPLC/QTOF MS.
Current China Pharmacopoeia standards for the Chinese patent medicines (CPMs) that contain one or several the same drug(s) employ case-dependent TLC or HPLC approaches to achieve qualitative identification. A qualitative "monomethod-heterotrait matrix" (MHM) strategy is thus proposed, by selective monitoring of multi-biomarkers, to achieve the identification of different CPMs. Carthamus tinctorius L. (safflower) is a reputable gynecological herbal medicine containing characteristic quinochalcone C-glycosides (QCGs) as the major bioactive components. Qualitative identification of safflower in diverse CPMs by selective monitoring of QCG markers was performed by use of the MHM strategy. Initially, 27 QCG analogs (involving 16 potentially new ones) were selectively characterized by product ion filtering (m/z 119.05) and integrated analysis of the negative mode MS(E) and Fast DDA data obtained on a UHPLC/QTOF mass spectrometer. Subsequently, by fingerprint analysis of 20 batches of safflower samples followed by a thermostable test, six QCGs (hydroxysafflor yellow A and its two isomers, anhydrosafflor yellow B, safflomin C, and isosafflomin C) were selected as the biomarkers for safflower. Then, a highly specific selective ion monitoring (SIM) method by recording centroided data was developed and applied to selectively profile six QCG biomarkers from 28 batches of CPM samples collected from versatile vendors. By reference to a standard SIM spectrum established using a home-made safflower reference extract, simultaneous identification of safflower in eleven different CPMs was accomplished with the unified sample preparation and a single UHPLC/QTOF-SIM method. The qualitative MHM strategy represents the novel methodology that facilitates the quality control of CPMs more efficiently.


Woodworm Bites in a 52-Year-Old Man.
A 52-year-old man was admitted for clinical counseling at the Campus Bio-Medico in Rome in the early days of August 2017. He presented with multiple erythemato-hemorrhagic papules localized on the abdomen (Figure 1), back, arms, and thighs (Figure 2). The wide eruption was characterized by an intense reddish color that disappeared with diascopy. The patient stated that the eruption had appeared overnight after helping his mother-in-law dispose of a piece of antique furniture from her country villa the previous afternoon. Unexpectedly for the patient, the eruption did not cause intense itching during the night (it became more severe upon waking the next morning), and it did not affect his wife.


Promotion of Cadaver-Based Military Trauma Education: Integration of Civilian and Military Trauma Systems.
For the past few decades, there has been an emphasis on encouraging the partnership of civilian and military trauma care systems which would allow military personnel to maintain competency in life-saving skills and gain experience prior to or in between deployments. Currently, there are only five primary military-civilian training centers in the United States. Thus, the majority of service members do not get the opportunity to train at these facilities prior to scheduled deployments. To bridge this gap, a joint military-civilian hands-on supplemental training program was established to allow deploying National Guard Combat Medics to practice life-saving techniques on human cadaver tissue. The purpose of this report is to provide the feedback survey from this pilot training session in hopes to expand and improve the curriculum and encourage partnerships between military and civilian trauma centers. Survey respondents include the 13 National Guard Combat Medic Specialists who attended the 6-hour voluntary training session. The survey asked qualitative and quantitative (using a 5-point Likert rating scale; 1 = insufficient/unacceptable/disagree; 5 = outstanding/exceeded expectations/strongly agree) questions regarding the structure of the session, likes and improvements about the classroom and cadaver lab portions, implementation into training, confidence in techniques before and after the session and overall rating of the session. This report has been reviewed and approved by the Institutional Review Board (IRB) at Rutgers University. Most attendees (12 of 13) agreed that the 6-hour total time length and division of classroom versus lab time was appropriate. Most attendees (12 of 13) agreed that this type of supplemental hands-on cadaver training should be a mandatory part of their medical training. The attendees' rated confidence in covered techniques was significantly increased from 3.77 ± 0.73 to 4.85 ± 0.38 (p < 0.01) before and after the session, respectively. The overall satisfaction rating of the session was 4.92 ± 0.28. This collaboration between military and civilian trauma care system was successful in giving National Guard combat medic specialists the opportunity to practice life-saving techniques on human tissue prior to deployment. This type of partnership can assist in maintaining readiness for trauma care and increasing the confidence of military pre-hospital providers in performing life-saving techniques.


Profile of cardiac disease in Cameroon and impact on health care services.
Cardiovascular diseases (CVD) have emerged as a major public health problem and impose an escalating burden on the health care system in Cameroon. The aim of the study was to investigate the preparedness of health care services for patients presenting with CVD in general and specifically, in St. Elizabeth catholic general hospital Shisong, cardiac centre. Between November 2009 and November 2011, a population of 8,389 adults and 706 children consulted the referral cardiac centre of St. Elizabeth Catholic General Hospital. The patients' age ranges between 5 days and 103 years old, with a mean of 48.7±18 years. Female represented 54.2% of the total population. Hypertension was diagnosed in 41.5% of patients. Isolated systolic hypertension was rarely found (4.2%) and 45.2% of patients were classified as class II according to the JNC7. Congestive heart failure was diagnosed in 29.6%. Forty-four percent of patients were in class III and 7% in class IV heart failure (NYHA). Arrhythmia was seen in 12.2% cases, with atrial fibrillation in 35.2%, followed by ventricular ectopic beats in 20.3%. Stable angina was diagnosed in 1.5%, and acute myocardial infarction 0.9%. In children, the prevalence of congenital heart disease was (4.3%). The disease the most detected was isolated ventricular septal defect, followed by tetralogy of Fallot. Post rheumatic valvulopathies were the main cause of heart failure in teenagers and young adults. Valve replacement with a mechanical valve was performed in 110 patients, valvuloplasty in eight patients, and surgical correction of congenital heart diseases in 105 cases. Our data, collected in a rural area, shows the high prevalence of hypertension in rural sub-Saharan Africa. Congestive heart failure mainly due to post rheumatic valvulopathies is common amongst children and young adults.


Idiopathic pulmonary fibrosis: emerging concepts on pharmacotherapy.
Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrosing disease of the distal air spaces of the lung of unknown aetiology. IPF is usually fatal with a median survival of < 3 years. There are currently no effective pharmacotherapeutic agents for the treatment of IPF. In this review, unifying concepts on the pathogenesis of IPF based on understanding of host responses to tissue injury are presented. These host responses involve tightly regulated and contextually orchestrated inflammatory and repair processes. Dysregulation of either of these processes can lead to pathological outcomes. Fibrosis results from an exaggerated or dysregulated repair process that proceeds 'uncontrolled' even after inflammatory responses have subsided. Disease heterogeneity may arise when inflammation and repair are in different (dys)regulatory phases, thus accounting for regional disparity. Usual interstitial pneumonia (UIP), the histopathological correlate of clinical IPF, represents a more fibrotic tissue reaction pattern and for which anti-inflammatory agents are ineffective. Emerging 'antifibrotic' drugs and strategies for UIP/IPF are discussed. The importance of accurately phenotyping a highly heterogeneous disease process that may require individualised and 'combined' therapies is emphasised.


HMB-45 reactivity in conventional uterine leiomyosarcomas.
We studied the human melanoma black-45 (HMB-45) reactivity in 25 uterine leiomyosarcomas including 23 conventional and 2 myxoid variants. Eleven tumors were poorly differentiated, and 14 were well to moderately differentiated. Nine uterine leiomyosarcomas labeled with HMB-45 in 10% or less of the tumor cells. Six were poorly differentiated and 3 were well differentiated. Our study indicates that 36% of conventional leiomyosarcomas focally express HMB-45. HMB-45 reactivity was more common in the poorly differentiated than in the well-differentiated group of leiomyosarcomas. In light of our findings and of those recently reported in the literature, we believe that the term PEComa should not be used for uterine leiomyosarcomas with clear cells or for conventional leiomyosarcomas that stain positively with HMB-45.


Effects of X-irradiation alone and in combination with ACNU on human glioblastoma cells in vitro.
The combined effects of x-irradiation and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloro-ethyl)-3-nitrosourea (ACNU) on multicellular glioblastoma A-7 spheroids were analyzed by means of cell survival and dose-response curves. The actual dose-response curve for small spheroids was almost identical to that estimated from the cell survival curve. It was strongly suggested that a small number of radiation-resistant cells, which were not detected in the cell survival curve, were present in large spheroids with central necrosis. The enhancing effect of ACNU was greater with large spheroids than with monolayer cells or small spheroids. A possible explanation for this is that ACNU is higher effective against the few radiation-resistant cells that may be present in larger spheroids.


Regulation of pattern recognition receptor signalling in plants.
Recognition of pathogen-derived molecules by pattern recognition receptors (PRRs) is a common feature of both animal and plant innate immune systems. In plants, PRR signalling is initiated at the cell surface by kinase complexes, resulting in the activation of immune responses that ward off microorganisms. However, the activation and amplitude of innate immune responses must be tightly controlled. In this Review, we summarize our knowledge of the early signalling events that follow PRR activation and describe the mechanisms that fine-tune immune signalling to maintain immune homeostasis. We also illustrate the mechanisms used by pathogens to inhibit innate immune signalling and discuss how the innate ability of plant cells to monitor the integrity of key immune components can lead to autoimmune phenotypes following genetic or pathogen-induced perturbations of these components.


The Usefulness of Functional Near-Infrared Spectroscopy for the Assessment of Post-Stroke Depression.
Background: Post-stroke depression (PSD) is the most common mood disorder following stroke and is also the main factor that limits the recovery and rehabilitation of patients with stroke. The prevalence of PSD is ~30%. Since there is no gold standard for the diagnosis and evaluation of PSD, it is important to raise awareness of PSD and to establish methods for its evaluation, early diagnosis, and treatment. In the field of psychiatry, functional near-infrared spectroscopy (fNIRS) has been used as a diagnostic tool for the measurement of oxygenated hemoglobin (oxy-Hb). This study aimed to assess whether fNIRS could be applied in the diagnosis and evaluation of PSD. Methods: We recruited 45 patients with stroke, who were admitted to Nagasaki Kita Hospital between May 2015 and April 2019. The 17-item Hamilton Rating Scale for Depression (HAMD17), which is considered to be a useful screening and evaluation tool for PSD, was used for the assessment of patients after stroke; moreover, oxy-Hb was measured in the pre-frontal cortex. The subjects were divided into two groups: the depressed group (n = 13) and the non-depressed group (n = 32). We evaluated the correlation between the oxy-Hb integral values and HAMD17 scores. Results: We investigated the relationship between the oxy-Hb integral values and HAMD17 total scores, and found a negative correlation between them (ρ = -0.331, P < 0.005). There was a significant difference in the oxy-Hb integral values during the activation task period between the depressed and non-depressed groups (3.16 ± 2.7 and 1.71 ± 2.4, respectively; P = 0.040). The results indicated that the patients of the depressed group showed lower oxy-Hb integral values and lower activation in the frontal lobe in comparison with the patients of the non-depressed group. Conclusion: The present study highlights that the measurement of oxy-Hb by using fNIRS is a useful methodology for the diagnosis of PSD in patients after stroke.


High PDL1/PDL2 gene expression correlates with worse outcome in primary mediastinal large B-cell lymphoma.
Primary mediastinal B-cell lymphoma (PMBL) is an uncommon entity of aggressive B-cell lymphoma with an unusually good prognosis, except for 10-15% of chemotherapy-refractory cases. To identify earlier these higher risk patients, we performed molecular characterization of a retrospective multicenter cohort of patients treated with firstline immunochemotherapy. The traits of the patients with gene-expression profiling data (n = 120) were as follows: median age of 34 years (range, 18-67 years); female sex, 58.3%; elevated lactate dehydrogenase, 82.5%; Eastern Cooperative Oncology Group performance status score of 0 to 1, 85.7%; Ann Arbor stage I/II, 55%; International Prognostic Index score of 1 to 2, 64.4%; and median metabolic tumor volume, 290.4 cm3 (range, 15.7-1147.5 cm3). Among all 137 markers tested for correlation with survival data, only programmed death-ligand (PDL) 1 and PDL2 expression showed a prognostic impact. Overall, both PDL1 and PDL2 genes were highly expressed in 37 patients (30.8%; PDL1high/PDL2high). The baseline clinical characteristics of patients with PDL1high/PDL2high were similar to those of other patients. In univariate analysis, PDL1high/PDL2high status was associated with poor progression-free survival (PFS) (hazard ratio [HR], 4.292) and overall survival (OS; HR, 8.24). In multivariate analysis, PDL1high/PDL2high status was an independent prognostic factor of adverse outcomes (PFS: HR, 5.22; OS: HR, 10.368). We validated these results in an independent cohort of 40 patients and confirmed the significant association between PDL1high/PDL2high status and inferior PFS (HR, 6.11). High PDL1/PDL2 gene expression defines a population with strong immune privilege and poorer outcomes from standard chemotherapy who might benefit from firstline checkpoint inhibitor therapy.


Use of calcium and secretin in the diagnosis of gastrinoma (Zollinger-Ellison syndrome).
Sixty-five patients with peptic ulcer disease were evaluated for gastrinoma (Zollinger-Ellison syndrome) by measuring changes in serum gastrin concentration after intravenous (i.v.) administration of calcium or secretin, or both. The presence of gastrinoma was established in all 20 patients whose serum gastrin increased by 395 pg/ml or more after i.v. calcium and in all 18 patients whose serum gastrin concentration increased by 110 pg/ml or more after i.v. secretin. The experience with these 65 patients shows that stimulation by calcium or secretin may confirm the presence of gastrinoma in cases where the diagnosis would otherwise remain obscure. Although a positive response to calcium or secretin is diagnostic for gastrinoma a negative response does not exclude this diagnosis. Stimulation with secretin is preferred for screening for gastrinoma because it is quicker and more reliable than calcium.


The InhA2 metalloprotease of Bacillus thuringiensis strain 407 is required for pathogenicity in insects infected via the oral route.
The entomopathogenic bacterium Bacillus thuringiensis is known to secrete a zinc metalloprotease (InhA) that specifically cleaves antibacterial peptides produced by insect hosts. We identified a second copy of the inhA gene, named inhA2, in B. thuringiensis strain 407 Cry(-). The inhA2 gene encodes a putative polypeptide showing 66.2% overall identity with the InhA protein and harboring the zinc-binding domain (HEXXH), which is characteristic of the zinc-requiring metalloproteases. We used a transcriptional inhA2'-lacZ fusion to show that inhA2 expression is induced at the onset of the stationary phase and is overexpressed in a Spo0A minus background. The presence of a reverse Spo0A box in the promoter region of inhA2 suggests that Spo0A directly regulates the transcription of inhA2. To determine the role of the InhA and InhA2 metalloproteases in pathogenesis, we used allelic exchange to isolate single and double mutant strains for the two genes. Spores and vegetative cells of the mutant strains were as virulent as those of the parental strain in immunized Bombyx mori larvae infected by the intrahemocoelic route. Exponential phase cells of all the strains displayed the same in vitro potential for colonizing the vaccinated hemocoel. We investigated the synergistic effect of the mutant strain spores on the toxicity of Cry1C proteins against Galleria mellonella larvae infected via the oral pathway. The spores of DeltainhA2 mutant strain were ineffective in providing synergism whereas those of the DeltainhA mutant strain were not. These results indicate that the B. thuringiensis InhA2 zinc metalloprotease has a vital role in virulence when the host is infected via the oral route.


Utility of Echocardiography in Detecting Silent Complications After Pediatric Catheter Ablations.
Although transcatheter arrhythmia ablation (TCA) has been performed in children for over two decades, guidelines for routine use of post-ablation transthoracic echocardiography (TTE) are absent. We sought to determine the efficacy of TTE after apparently uneventful TCA procedures in detecting adverse findings and identify predisposing factors. A retrospective review of clinical and procedural data on patients who underwent TCA for supraventricular arrhythmias from 2000 to 2015 was performed. Pre- and post-ablation TTE data were reviewed. All patients were followed at 1 week, 6 and 12 months post-TCA. A repeat TTE was performed at 12 months on patients in whom post-TCA abnormalities were found. Patients were divided into two groups: those with and without adverse TTE findings and comparative analysis between variables was performed. Data on 252 patients, 52% males, mean age 14 ± 3 years were analyzed. New onset or worsening atrioventricular valve regurgitation occurred in 17 (6.7%), a small pericardial effusion in 3 (1.2%) and worsened ventricular function in 2 patients (0.8%). Patients in the complication group had higher mean number of ablations (22.6 ± 15.3 vs. 16.8 ± 9.2, p 0.001) and required longer duration of ablation (sec) (254.6 ± 256.4 vs. 180.9 ± 158.9, p < 0.001). TCA location (including coronary sinus), energy source, arrhythmia substrate, and a trans-septal approach were noncontributory to any adverse findings. Routine post-ablation TTE uncovers asymptomatic self-resolving abnormalities that typically do not require any intervention.


Angiogenesis therapy in ischemic disease.
The ability of organisms to spontaneously develop collateral vessels represents an important response to vascular occlusive diseases that determines the severity of residual tissue ischemia. Neovascularization of ischemic cardiac or skeletal muscle may be sufficient to preserve tissue integrity and/or function, and may thus be considered to be therapeutic. Innovative gene technologies and advances in animal modeling have enabled research scientists to develop therapeutic angiogenesis strategies applied in animal models of limb or myocardial ischemia and in treatment of patients with peripheral vascular obstruction or coronary artery diseases. Several therapeutic strategies have been proposed and tested even at the clinical level. Recent studies have established the feasibility of using recombinant angiogenic growth factors (mainly VEGF and FGF) to enhance angiogenesis in patients with limb or myocardial ischemia. Angiogenesis therapies using cells as a support for growth factor delivery or using endothelial progenitor cells which may directly participate in the angiogenic process have also been developed. Finally, one potential alternative strategy may be the use of drugs with pro-angiogenic activity, available in an oral formulation and which are currently administered to patients for treatment of different pathologies. All strategies of angiogenesis therapy currently being tested have the potential to be effective in the treatment of ischemic disease. However, such strategies may cause harmful side effects which emphasize the need to be aware of the biological effects of each angiogenic agent proposed for clinical studies.


Modeling Variability in the Progression of Huntington's Disease A Novel Modeling Approach Applied to Structural Imaging Markers from TRACK-HD.
We present a novel, general class of disease progression models for Huntington's disease (HD), a neurodegenerative disease caused by a cytosine-adenine-guanine (CAG) triplet repeat expansion on the huntingtin gene. Models are fit to a selection of structural imaging markers from the TRACK 36-month database. The models are of mixed effects type and should be useful in predicting any continuous marker of HD state as a function of age and CAG length (the genetic factor that drives HD pathology). The effects of age and CAG length are modeled using flexible regression splines. Variability not accounted for by age, CAG length, or covariates is modeled using terms that represent measurement error, population variability (random slopes/intercepts), and variability due to the dynamics of the disease process (random walk terms). A Kalman filter is used to estimate variances of the random walk terms.


Multifactorial Modulation of Food-Induced Anaphylaxis.
Prevalence of food-induced anaphylaxis increases progressively and occurs in an unpredictable manner, seriously affecting the quality of life of patients. Intrinsic factors including age, physiological, and genetic features of the patient as well as extrinsic factors such as the intake of drugs and exposure to environmental agents modulate this disorder. It has been proven that diseases, such as mastocytosis, defects in HLA, or filaggrin genes, increase the risk of severe allergic episodes. Certain allergen families such as storage proteins, lipid transfer proteins, or parvalbumins have also been linked to anaphylaxis. Environmental factors such as inhaled allergens or sensitization through the skin can exacerbate or trigger acute anaphylaxis. Moreover, the effect of dietary habits such as the early introduction of certain foods in the diet, and the advantage of the breastfeeding remain as yet unresolved. Interaction of allergens with the intestinal cell barrier together with a set of effector cells represents the primary pathways of food-induced anaphylaxis. After an antigen cross-links the IgEs on the membrane of effector cells, a complex intracellular signaling cascade is initiated, which leads cells to release preformed mediators stored in their granules that are responsible for the acute symptoms of anaphylaxis. Afterward, they can also rapidly synthesize lipid compounds such as prostaglandins or leukotrienes. Cytokines or chemokines are also released, leading to the recruitment and activation of immune cells in the inflammatory microenvironment. Multiple factors that affect food-induced anaphylaxis are discussed in this review, paying special attention to dietary habits and environmental and genetic conditions.


Data-driven gradient regularization for quasi-Newton optimization in iterative grating interferometry CT reconstruction.
Grating interferometry CT (GI-CT) is a promising technology that could play an important role in future breast cancer imaging. Thanks to its sensitivity to refraction and small-angle scattering, GI-CT could augment the diagnostic content of conventional absorption-based CT. However, reconstructing GI-CT tomographies is a complex task because of ill problem conditioning and high noise amplitudes. It has previously been shown that combining data-driven regularization with iterative reconstruction is promising for tackling challenging inverse problems in medical imaging. In this work, we present an algorithm that allows seamless combination of data-driven regularization with quasi-Newton solvers, which can better deal with ill-conditioned problems compared to gradient descent-based optimization algorithms. Contrary to most available algorithms, our method applies regularization in the gradient domain rather than in the image domain. This comes with a crucial advantage when applied in conjunction with quasi-Newton solvers: the Hessian is approximated solely based on denoised data. We apply the proposed method, which we call GradReg, to both conventional breast CT and GI-CT and show that both significantly benefit from our approach in terms of dose efficiency. Moreover, our results suggest that thanks to its sharper gradients that carry more high spatial-frequency content, GI-CT can benefit more from GradReg compared to conventional breast CT. Crucially, GradReg can be applied to any image reconstruction task which relies on gradient-based updates.


The complete chloroplast genome of Rhodobryum laxelimbatum (Hampe ex Ochi) Z. Iwatsuki and T. J. Koponen.
Rhodobryum laxelimbatum (Bryophyta, Bryaceae) is one of the folk medicine resources in Southwest China, which has excellent potential for application in treating cardiovascular diseases. In this study, R. laxelimbatum was sequenced by high-throughput sequencing technology. The complete chloroplast genome is 124,632 bp in length with a quadripartite structure. Two inverted repeat regions are 9837 bp, separated by a large single copy region of 86,444 bp and a small single copy region of 18,514 bp. It encodes 118 unique genes, including 82 protein-coding genes, 32 tRNA genes, and four rRNA genes. The phylogenetic tree was constructed based on the complete chloroplast genome sequences of 18 bryophytes, downloaded from GenBank and acquired in this study. The phylogenetic analysis strongly indicated that R. laxelimbatum was the sister group of the clade which consists of Mnium marginatum, Pohlia cruda and Pohlia nutans. The R. laxelimbatum chloroplast genome sequence provides new genomic resources, which will improve its research, conservation, and application in the future.


UBQLN1 deficiency mediates telomere shortening and IPF through interacting with RPA1.
Premature telomere shortening is a known factor correlated to idiopathic pulmonary fibrosis (IPF) occurrence, which is a chronic, progressive, age-related disease with high mortality. The etiology of IPF is still unknown. Here, we found that UBQLN1 plays a key role in telomere length maintenance and is potentially relevant to IPF. UBQLN1 involves in DNA replication by interacting with RPA1 and shuttling it off from the replication fork. The deficiency of UBQLN1 retains RPA1 at replication fork, hinders replication and thus causes cell cycle arrest and genome instability. Especially at telomere regions of the genome, where more endogenous replication stress exists because of G rich sequences, UBQLN1 depletion leads to rapid telomere shortening in HeLa cells. It revealed that UBQLN1 depletion also shortens telomere length at mouse lung and accelerates mouse lung fibrosis. In addition, the UBQLN1 expression level in IPF patients is downregulated and correlated to poor prognosis. Altogether, these results uncover a new role of UBQLN1 in ensuring DNA replication and maintaining telomere stability, which may shed light on IPF pathogenesis and prevention.


US Evaluation of Juvenile Idiopathic Arthritis and Osteoarticular Infection.
Juvenile idiopathic arthritis (JIA) and osteoarticular infection can cause nonspecific articular and periarticular complaints in children. Although contrast material-enhanced magnetic resonance imaging is the reference standard imaging modality, musculoskeletal ultrasonography (US) is emerging as an important adjunct imaging modality that can provide valuable information relatively quickly without use of radiation or the need for sedation. However, diagnostic accuracy requires a systemic approach, familiarity with various US techniques, and an understanding of maturation-related changes. Specifically, the use of dynamic, Doppler, and/or multifocal US assessments can help confirm sites of disease, monitor therapy response, and guide interventions. In patients with JIA, ongoing synovial inflammation can lead to articular and periarticular changes, including synovitis, tenosynovitis, cartilage damage, bone changes, and enthesopathy. Although these findings can manifest in adult patients with rheumatoid arthritis, important differences and pitfalls exist because of the unique changes associated with an immature and maturing skeleton. In patients who are clinically suspected of having osteoarticular infection, the inability of US to evaluate the bone marrow decreases its sensitivity. Therefore, the US findings should be interpreted with caution because juxtacortical inflammation is suggestive, but neither sensitive nor specific, for underlying osteomyelitis. Similarly, the absence of a joint effusion makes septic arthritis extremely unlikely but not impossible. US findings of JIA and osteoarticular infection often overlap. Although certain clinical scenarios, laboratory findings, and imaging appearances can favor one diagnosis over the other, fluid analysis may still be required for definitive diagnosis and optimal treatment. US is the preferred modality for fluid aspiration and administering intra-articular corticosteroid therapy. © RSNA, 2017.


The effects of chronic illness on children and their families: an overview.
Between 10% and 20% of children suffer from chronic illness, the severity and impact of which vary considerably. Treatment aims to reduce the potentially negative effects of the illness on the child and the family and to help them achieve a normal life style. It is increasingly clear that the way in which children cope with chronic illness appears to be influenced by the illness, the child's personality, and characteristics of the family and social environment. Recent theoretical approaches suggest that the risk of maladjustment increases when stress increases. More sophisticated methods of sampling and measurement have resulted in recent research that presents a less negative picture of the psychosocial implication of chronic illness. In this article, I give an overview of the effect of chronic illness on children and their families, and I suggest directions for future research.


A statistical approach to aid examiners in the forensic analysis of handwriting.
We develop a statistical approach to model handwriting that accommodates all styles of writing (cursive, print, connected print). The goal is to compute a posterior probability of writership of a questioned document given a closed set of candidate writers. Such probabilistic statements can support examiner conclusions and enable a quantitative forensic evaluation of handwritten documents. Writing is treated as a sequence of disjoint graphical structures, which are extracted using an automated and open-source process. The graphs are grouped based on the similarity of their shapes through a K-means clustering template. A person's writing pattern can be characterized by the rate at which graphs are emitted to each cluster. The cluster memberships serve as data for a Bayesian hierarchical model with a mixture component. The rate of mixing between two parameters in the hierarchy indicates writing style.


A Visible-Light-Mediated Radical Smiles Rearrangement and its Application to the Synthesis of a Difluoro-Substituted Spirocyclic ORL-1 Antagonist.
A visible-light-mediated radical Smiles rearrangement has been developed to address the challenging synthesis of the gem-difluoro group present in an opioid receptor-like 1 (ORL-1) antagonist that is currently in development for the treatment of depression and/or obesity. This method enables the direct and efficient introduction of the difluoroethanol motif into a range of aryl and heteroaryl systems, representing a new disconnection for the synthesis of this versatile moiety. When applied to the target compound, the photochemical step could be conducted on 15 g scale using industrially relevant [Ru(bpy)3Cl2] catalyst loadings of 0.01 mol %. This transformation is part of an overall five-step route to the antagonist that compares favorably to the current synthetic sequence and demonstrates, in this specific case, a clear strategic benefit of photocatalysis.


Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study.
Observational studies and clinical trials have suggested that periconceptional use of folic acid can reduce the risk of birth defects other than neural tube defects (NTDs). Using data reported by states to the National Birth Defects Prevention Network, we examined whether folic acid fortification might have decreased the prevalence of other specific birth defects. For each of 16 birth defect categories selected for study, birth prevalence for two time periods was calculated with data submitted from a number of states in 1995-1996 ("pre-fortification") and 1999-2000 ("post-fortification"). Changes in birth prevalence between the two time periods were assessed by calculating prevalence ratios and 95% confidence intervals for each defect, and compared by maternal race/ethnicity and availability of prenatally diagnosed cases. We confirmed previously reported reductions in the birth prevalence of NTDs. In addition, we found modest, yet statistically significant, decreases in the birth prevalence for transposition of the great arteries(12%), cleft palate only (12%), pyloric stenosis (5%), upper limb reduction defects (11%), and omphalocele (21%). More substantial subgroup decreases were observed for renal agenesis among programs that conduct prenatal surveillance (28%), for common truncus among Hispanics (45%), and for upper limb reduction defects among Hispanics (44%). There were modest yet significant increases in the prevalence of obstructive genitourinary defects (12%) and Down syndrome (7%), but not among programs conducting prenatal surveillance for these defects. These results suggest some modest benefit from the folic acid fortification on the prevalence of a number of non-NTD birth defects.


Optimized highly efficient multilayer-coated blazed gratings for the tender X-ray region.
The optimized design of multilayer-coated blazed gratings (MLBG) for high-flux tender X-ray monochromators was systematically studied by numerical simulations. The resulting correlation between the multilayer d-spacing and grating blaze angle significantly deviated from the one predicted by conventional equations. Three high line density gratings with different blaze angles were fabricated and coated by the same Cr/C multilayer. The MLBG with an optimal blaze angle of 1.0° showed a record efficiency reaching 60% at 3.1 keV and 4.1 keV. The measured efficiencies of all three gratings were consistent with calculated results proving the validity of the numerical simulation and indicating a more rigorous way to design the optimal MLBG structure.


Method for individualized evaluation of antiemetic effect induced by 5-HT3 receptor antagonist.
5-HT3 receptor antagonists are widely used for prevention of chemotherapy-induced nausea and vomiting, though their antiemetic effects vary among patients. We investigated a method for evaluation of antiemetic effects in individual patients. We used the 5-HT3 receptor occupancy of serotonin for our evaluation, which was estimated based on the plasma concentration of granisetron and concentration of serotonin near the 5-HT3 receptor in the small intestine, obtained by measuring the urinary concentrations of granisetron and 5-hydroxyindoleacetic acid (5-HIAA)/creatinine (Cre). The mean cumulative percent for urinary excretion of granisetron at 24 h after administration and coefficient of variation were 16.19 ± 6.30% and 38.91%, respectively. The time course of urinary concentration of 5-HIAA/Cre also varied among the patients. The value for 5-HT3 receptor occupancy of serotonin without granisetron was higher than that prior to administration (blank), thus most treated patients had the possibility of induced emesis. In contrast, that with granisetron was lower than the blank value, indicating that those treated patients would not develop emesis. Furthermore, the estimated 5-HT3 receptor occupancy of serotonin in the small intestine and actual individual patient condition corresponded well, showing the validity of our method. Our results suggest that it is possible to evaluate individual antiemetic effects by estimating the 5-HT3 receptor occupancy of serotonin in the small intestine based on plasma concentrations of granisetron and serotonin near the 5-HT3 receptor in the small intestine using noninvasive urine samples. This method of individual evaluation is considered to be useful and effective.


Intracystic papillary carcinoma of the breast in a 21-year old premenopausal Nigerian woman: a case report.
We report the case of a 21-year-old Nigerian woman who presented to us with features of intracystic papillary carcinoma, a rare form of breast cancer usually seen in postmenopausal women in their sixth to eighth decades of life. To the best of our knowledge, there has been only one other case report of this lesion occurring in women in their second decade of life.Physical examination showed a well-defined mass, 54 mm in diameter, in the upper proximal quadrant of the right breast close to the areola, histologically composed of monotypic epithelial cells disposed in solid, cystic, and papillary patterns. A diagnosis of intracystic papillary carcinoma was made because of the presence of intracystic arborization of the fibrovascular stroma, a monotonous cell population, the presence of mitoses, and the lack of myoepithelial cells determined by immunohistochemistry using calponin and p63 stains. Estrogen receptor status was positive while progesterone status and HER-2-neu receptor status were negative.The patient has survived for 12 months without any sign of recurrence after the last surgical resection of the tumor.


Association between female breast cancer and cutaneous melanoma.
Epidemiologic studies have provided suggestive evidence of a link between cutaneous melanoma (CM) and breast cancer (BC). Moreover, carriers of mutations in the breast cancer predisposition gene, BRCA2, have an increased risk of melanoma while carriers of mutations in the melanoma susceptibility gene, CDKN2A, exhibit a higher than expected risk of breast cancer. These findings raise the possibility that pathways involved in the development of CM and BC overlap and that survivors of one cancer may be prone to develop the other. To this end, we set out to determine if survivors of female BC in the Surveillance, Epidemiology and End Result (SEER) database are at increased risk for CM and vice versa. We followed female BC patients registered in the 1973-1999 SEER database for development of a second CM and female CM patients for the development of a second BC. The expected number of cases was then compared to the observed number of cases using standardized incidence ratios. Overall, we found a modest but statistically significant increased risk of CM among female BC survivors and vice versa. Among young BC patients, we observed a 46% elevated risk of a second CM. Women who underwent radiation therapy exhibited a 42% increased risk for CM. The risks of BC among female CM survivors and CM among BC survivors were also elevated, albeit to a much lesser degree (overall, 11% and 16%, respectively). We found a mutual association between female BC and CM. The elevated risk for CM, especially among younger BC patients, suggests that the genetic observations from high-risk groups may also be operative at a much lower level in the general BC population.


Pursuing Humanistic Medicine in a Technological Age.
The humanistic practice of medicine requires that the practitioner have sufficient time and appropriate focus. Both elements, however, are under assault by the high-speed, distraction-filled environment within which primary care is delivered today. Despite or perhaps because of modern medicine's technological advances, the potentially healing bond between doctor and patient is being frayed and the quality of care consequently degraded.


de Quervain's Tenosynovitis and Radial Styloid Osseous Changes.
This study aimed to determine the radial styloid osseous changes observed on posteroanterior wrist radiographs of patients with de Quervain's tenosynovitis who required surgery or conservative treatment. The surgically treated group included 24 patients with de Quervain's tenosynovitis. The conservative treatment group and the healthy control group each comprised 24 age- and sex-matched subjects. We evaluated the presence of bone apposition, periosteal reaction, sclerosis, osteopenia, erosion, and contour bulge in the epiphyseal remnant at the radial styloid. The incidences of abnormal radiographic findings were compared between these three groups. The correlation of radial styloid bony changes with the duration of symptoms was also analyzed. No significant differences were found between the three groups in terms of periosteal reaction, erosion, and contour bulge at the epiphysial remnant. Significant differences were found between the three groups in the incidence of bone apposition, sclerosis, and osteopenia (p < 0.001). Bone apposition incidence in the surgically and conservatively treated groups was significantly higher than that in the control group (p < 0.001). Sclerosis and osteopenia significantly differed between the surgically and conservatively treated groups (p < 0.001, p = 0.002, respectively). No significant association was observed between the duration of symptoms and the radial styloid osseous changes (p > 0.05). We found a variable incidence of abnormal radiographic findings on the radial styloid in patients with de Quervain's tenosynovitis and asymptomatic individuals. The presence of sclerosis and osteopenia may be potential risk factors for patients who do not respond to conservative treatment and need surgical intervention.


Quantification of the risk and predictors of hyperkalemia in patients with left ventricular dysfunction: a retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) trials.
Limited data are available to predict the occurrence of hyperkalemia. Risk assessment is complicated by the lack of consistency of definition between trials. We conducted a retrospective analysis of the SOLVD to evaluate the incidence of hyperkalemia and the value of several baseline characteristics as predictors of hyperkalemia in patients with left ventricular dysfunction. The incidence of hyperkalemia was 6.0% and 1.1% using a definition of > or = 5.5 and > or = 6.0 mmol/L, respectively. Independent predictors of hyperkalemia (> or = 5.5 mmol/L) were randomization to enalapril, baseline serum creatinine, serum potassium, New York Heart Association functional class III or IV, a history of diabetes, and atrial fibrillation (all P < .05). The use of loop diuretics was also associated with an increased risk of hyperkalemia but only in patients included in the SOLVD prevention trial. Similar results were obtained when renal function was evaluated using the estimated creatinine clearance. The definition of hyperkalemia is important when evaluating its incidence in clinical trials. Renal dysfunction, baseline serum potassium, diabetes, atrial fibrillation, New York Heart Association functional class, and treatment with an angiotensin-converting enzyme inhibitor are factors associated with the development of hyperkalemia in patients with left ventricular dysfunction. More specifically, our results suggests that before initiating drugs that can cause hyperkalemia in patients with heart failure, a strong consideration should be given to calculate creatinine clearance and that patients with a creatinine clearance < 60 mL/min should undergo a close monitoring of their serum potassium to prevent the development of hyperkalemia.


Are Symptoms Sufficient in the Decision to Start Antibiotics in Tonsillopharyngitis?
Unnecessary use of antibiotics is one of the causes of antibiotic resistance. Rapid Antigen Test (RAT) is recommended to prevent unnecessary use of antibiotics by providing bacteria/virus isolation in patients with tonsillopharyngitis. However, in patients with typical symptoms, false-negative test results may lead to doubt in doctors. In this study, we aimed to evaluate the relationship between patients' symptoms and RAT results. In this study, we chose the patients that referred to the University of Health Sciences (SBÜ) Şişli Hamidiye Etfal Training and Research Hospital Family Medicine Polyclinics and got a diagnosis of tonsillopharyngitis with RAT. This study was conducted by a retrospective file scanning method. We examined the age, sex, symptoms, RAT results and throat culture results of the patients. SPSS 15.0 for Windows program was used for the statistical analysis. The level of statistical significance was accepted as p<0.05. In this study, the RAT of 265 patients and the throat culture of 141 patients were examined. We found RAT positivity as 28.7%, Group A Beta Hemolytic Streptococcus (AGBHS) detection rate in throat culture was 22.5%, and the antibiotic prescription rate was 37%. There were 32 patients with AGBHS positivity in throat culture. Twenty-seven of them got RAT positivity, too. When symptoms and RAT positivity were examined, there was no significant relationship between RAT positivity and fever higher than 38 oC, but RAT was more often positive in patients with a fever higher than 38 oC. On the other hand, there is a statistically significant relationship between RAT positivity and the presence of tonsillar exudate (p=0.000). When the relationship between symptoms and RAT according to age groups was examined, the presence of LAP and tonsillitis were significant (p=0.000; p=0.001). In the age group of 18 years and over, the presence of tonsillar exudates was significant (p=0.001). In our study, tonsillar exudate was a common symptom in both age groups of <18, and ≥18 years of age; at the same time, there is a statistically significant relation with RAT. Tonsillar exudates are not seen only in bacterial infections but also in viral infections. Thus, we think that antibiotics should not be started based on symptoms, and RAT should be used effectively.


Obese Individuals Show Disrupted Dynamic Functional Connectivity between Basal Ganglia and Salience Networks.
Previous functional magnetic resonance imaging (fMRI) studies have showed obesity (OB)-related alterations in intrinsic functional connectivity (FC) within and between different resting-state networks (RSNs). However, few studies have examined dynamic functional connectivity (DFC). Thus, we employed resting-state fMRI with independent component analysis (ICA) and DFC analysis to investigate the alterations in FC within and between RSNs in 56 individuals with OB and 46 normal-weight (NW) controls. ICA identified six RSNs, including basal ganglia (BG), salience network (SN), right executive control network/left executive control network, and anterior default-mode network (aDMN)/posterior default-mode network. The DFC analysis identified four FC states. OB compared with NW had more occurrences and a longer mean dwell time (MDT) in state 2 (positive connectivity of BG with other RSN) and also had higher FC of BG-SN in other states. Body mass index was positively correlated with MDT and FCs of BG-aDMN (state 2) and BG-SN (state 4). DFC analysis within more refined nodes of RSNs showed that OB had more occurrences and a longer MDT in state 1 in which caudate had positive connections with the other network nodes. The findings suggest an association between caudate-related and BG-related positive FC in OB, which was not revealed by traditional FC analysis, highlighting the utility of adding DFC to the more conventional methods.


The ever-increasing diversity in mouse lemurs: three new species in north and northwestern Madagascar.
Mouse lemurs (Microcebus spp.) are the world's smallest primates and endemic to Madagascar. Several recent taxonomic revisions resulted in an extraordinary increase of recognized species. What still was considered as being two species at the beginning of the 20th century is currently recognized as 12 taxa. Based on fur coloration pattern, they can be divided into grayish and reddish forms. Two major models have been proposed to explain the extensive speciation events in the Malagasy fauna. The best known suggests that major rivers and mountains combine to act as effective barriers to gene flow and thereby facilitate allopatric speciation processes. A more recent model used an analysis of watersheds in the context of Quaternary climatic shifts to explain the process of explosive speciation on the island. We tested these two models by covering the areas between all major rivers (n=8) in northwestern and northern Madagascar. Mouse lemurs were systematically caught, sampled and morphometrically characterized in 25 sites (with 2-49 individuals per site and species). A complete phylogeny was constructed on the basis of the sequences of three mitochondrial loci (in total 1296 bp). The phylogenetic data revealed a previously unknown biodiversity with three new mouse lemur species among the reddish forms, each having a very small distribution, i.e., being restricted to only one Inter-River-System (IRS). Morphometric analyses underlined their distinctiveness and a brief formal species description is provided. In contrast to the reddish forms, grayish forms have a very low species diversity coupled with broad distributions that cover more than one IRS. These differences among the species are discussed as outcome of divergent colonization scenarios. Elements of both biogeographic models are combined in a new hypothesis that aims to explain the speciation process leading to the present distribution of mouse lemurs in Madagascar.


The Gene Expression Profile and DNA Methylation Pattern of CDH1 and DNMT1 Genes in Acute Promyelocytic Leukemia (APL).
DNA methylation is an epigenetic modification that has the ability to alter gene expression and function. These epigenetic changes have been associated with the development of cancer. Previous research has found that DNA methylation patterns can predict disease prognosis for patients with Acute Promyelocytic Leukemia (APL). The role of DNMT1 and CDH1 in regulating the extension of cells are studied in this study. DNA was extracted from peripheral blood samples of APL patients and treated with bisulfite. DNMT1 and CDH1 gene promoter methylation was subsequently analyzed using methylation-specific PCR (MSP). Real-time PCR was used to measure the expression level of DNMT1 and CDH1 genes. Partial methylation of the CDH1 gene promoter was detected in 20% of APL patients and an unmethylated status was detected in 80% of patient samples. Additionally, an unmethylated status in the DNMT1 gene promoter was detected in 100% of APL patient samples. Our study found the CDH1 gene promoter to be unmethylated in almost all APL patients, while the DNMT1 promoter was unmethylated in all APL patients. Furthermore, we observed an increase in both CDH1 and DNMT1 gene expression in APL patients compared to healthy controls. These findings suggest that DNMT1 may not have a specific role in inhibiting CDH1 gene expression in APL. Applying higher resolution techniques would help to better uncover the DNA methylation patterns in patients with APL. Further research is required to determine the role of DNA methylation and CDH1 and DNMT1 gene expression in APL.


Uptake of channel catfish virus from water by channel catfish and bluegills.
Radiolabeled channel catfish virus entered the gills of juvenile channel catfish (Ictalurus punctatus) and was then concentrated in the gut and the liver over 48 hours. Diminution of radioactivity was not detected in these tissues over the course of the experiment. Bluegills (Lepomis macrochirus) were capable of clearing the virus during a period of 48 hours. [3H]Thymidine alone had a different distribution in the channel catfish than did labeled virus.


Investigation on electrical surface modification of waste to energy ash for possible use as an electrode material in microbial fuel cells.
With the world population expected to reach 8.5 billion by 2030, demand for access to electricity and clean water will grow at unprecedented rates. Municipal solid waste combusted at waste to energy (WtE) facilities decreases waste volume and recovers energy, but yields ash as a byproduct, the beneficial uses of which are actively being investigated. Ash is intrinsically hydrophobic, highly oxidized, and exhibits high melting points and low conductivities. The research presented here explores the potential of ash to be used as an electrode material for a microbial fuel cell (MFC). This application requires increased conductivity and hydrophilicity, and a lowered melting point. Three ash samples were investigated. By applying an electric potential in the range 50-125 V across the ash in the presence of water, several key property changes were observed: lower melting point, a color change within the ash, evidence of changes in surface morphologies of ash particles, and completely wetting water-ash contact angles. We analyzed this system using a variety of analytical techniques including sector field inductively coupled plasma mass spectrometry, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and tensiometry. Ability to make such surface modifications and significant property changes could allow ash to become useful in an application such as an electrode material for a MFC.


Development of a resonant screw-driven piezoelectric motor operating in single-mode vibration.
A resonant screw-driven piezoelectric motor operating in single-mode vibrations is proposed, designed, manufactured, and studied. The motor is constructed with a stator and a threaded rotor. The stator consists of a hollow parallelogram metal elastomer and two piezoelectric ceramic plates. The motor is excited by a single-phase signal to produce two separate vibration modes: the first expansion mode (B1 mode) and the second expansion mode (B2 mode). Each mode drives the threaded rotor in one direction, and the bidirectional motion is achieved by switching the two modes. The construction is designed, and modal simulation is performed using finite element software to determine the structural parameters. A frequency-domain analysis is performed to obtain the frequency response characteristics, and the motion trajectories of the stator are obtained using transient analysis. Finally, a prototype is produced, and experiments are conducted. Experimental results indicate that the no-load speeds of the motor under the 200 Vp-p voltage excitation are 1.67 and 1.04 mm/s in the two modes, which correspond to maximum loads of 35 and 20 mN, respectively.


Divergent synthesis of N-heterocycles by Pd-catalyzed controllable cyclization of vinylethylene carbonates.
Here, we report a palladium-catalyzed controllable cyclization of vinyl ethylene carbonates that proceeds through formal migration [2+3] and [5+2] cycloadditions, respectively, under mild conditions. The transformation described here affords a series of synthetically versatile 5,7-membered N-heterocycles which are found in natural products and pharmaceuticals with biological and medicinal properties.


[Retroperitoneal rupture of the duodenum caused by closed abdominal injury].
Preoperative diagnosis of retroperitoneal rupture of the duodenum is very difficult. Radiographical observation of air surrounding the right kidney or psoas muscle is of great assistance in this respect, but may only be expected in 30% of cases. Examination of the first segment of the digestive tract with the aid of "gastropgrafin" is advised. With the abdomen open, the presence of air, haematoma or bile in the transverse mesocolon or mesentery of the small intestine may be noted. In most cases, the breach can be closed with a double layer, leaving a drainage tube in the retroperitoneum. Measures than can be taken when suturing is unfeasable are also described.


[Determination of 193 pesticide residues in vegetables and fruits by gas chromatography-mass spectrometry].
On the basis of optimization of solid phase extraction adsorbent, eluting solvent types and amounts, a gas chromatography-mass spectrometric method was developed for the determination of 193 pesticide residues in vegetables and fruits. The analytes were extracted from the samples using acetonitrile. The extract was cleaned-up with a C18/PSA solid-phase extractor, eluted by acetonitrile and analyzed by GC-MS under selected ion monitoring (SIM) mode using triphenyl phosphate (TPP) as internal standard. The linear range was from 10 to 1 000 microg/L for 130 pesticides, from 20 to 1 000 microg/L for 34 pesticides, from 50 to 1 000 microg/L for 26 pesticides, from 100 to 1 000 microg/L for the other 3 pesticides with the good correlation coefficients (r > or = 0.996 7). The limits of detection were 0.04 - 8.26 microg/kg. The mean recoveries of the pesticides were 71.6% -117.9%. The relative standard deviations were 3.0% - 11.8%. This method is simple, rapid, sensitive and specific. It is appropriate for the simultaneous identification and quantification of the multi-residues in fruits and vegetables.


[A CASE OF DEXTRANOMER-HYALURONIC ACID COPOLYMER (Deflux®) IMPLANTS CALCIFICATION MIMICKING DISTAL URETERAL CALCULI].
Since 2011, endoscopic correction of vesicoureteral reflux using dextranomer-hyaluronic acid copolymer (Deflux®) has been widely accepted in Japan due to its safety and minimally invasive nature. However, long-term complications are unknown. We present a case of Deflux® implants calcification mimicking distal ureteral calculi in a 12-year-old boy with a history of Deflux® injection performed at three years of age for primary VUR. We should be aware of this complication to avoid misdiagnosis and unnecessary invasive examination such as radiological imaging or endoscopy.


Chiral Phosphoric Acid Catalyzed Asymmetric Addition of 2-(Vinyloxy)ethanol to Imines and Applications of the Products.
Chiral nitrogen-containing molecules such as chiral amines, azetidines, and 2-substituted tetrahydroquinolines are important privileged scaffolds in medicinal chemistry. In this paper, an efficient and highly enantioselective chiral phosphoric acid catalyzed asymmetric addition of 2-(vinyloxy)ethanol to imines has been developed for the first time, providing the corresponding chiral amines containing dioxolane acetals that can transform into useful chiral N-heterocycles including azetidines and 2-substituted tetrahydroquinolines with excellent optical purity.


Mutual impacts and interactions of antibiotic resistance genes, microcystin synthetase genes, graphene oxide, and Microcystis aeruginosa in synthetic wastewater.
The physiological impacts and interactions of antibiotic resistance gene (ARG) abundance, microcystin synthetase gene expression, graphene oxide (GO), and Microcystis aeruginosa in synthetic wastewater were investigated. The results demonstrated that the absolute abundance of sul1, sul2, tetW, and tetM in synthetic wastewater dramatically increased to 365.2%, 427.1%, 375.2%, and 231.7%, respectively, when the GO concentration was 0.01 mg/L. Even more interesting is that the sum gene copy numbers of mcyA-J also increased to 243.2%. The appearance of GO made the significant correlation exist between ARGs abundance and mcyA-J expression. Furthermore, M. aeruginosa displayed better photosynthetic performance and more MCs production at 0.01 mg/L GO. There were 65 pairs of positive correlations between the intracellular differential metabolites of M. aeruginosa and the abundance of sul1, sul2, tetM, and tetW with various GO concentrations. The GO will impact the metabolites and metabolic pathway in M. aeruginosa. The metabolic changes impacted the ARGs, microcystin synthetase genes, and physiological characters in algal cells. Furthermore, there were complex correlations among sul1, sul2, tetM, tetW, mcyA-J, MCs, photosynthetic performance parameters, and ROS. The different concentration of GO will aggravate the hazards of M. aeruginosa by promoting the expression of mcyA-J, producing more MCs; simultaneously, it may cause the spread of ARGs.


High-frequency epigenetic repression and silencing of retroviruses can be antagonized by histone deacetylase inhibitors and transcriptional activators, but uniform reactivation in cell clones is restricted by additional mechanisms.
Integrated retroviral DNA is subject to epigenetic gene silencing, but the viral and host cell properties that influence initiation, maintenance, and reactivation are not fully understood. Here we describe rapid and high-frequency epigenetic repression and silencing of integrated avian sarcoma virus (ASV)-based vector DNAs in human HeLa cells. Initial studies utilized a vector carrying the strong human cytomegalovirus (hCMV) immediate-early (IE) promoter to drive expression of a green fluorescent protein (GFP) reporter gene, and cells were sorted into two populations based on GFP expression [GFP(+) and GFP(-)]. Two potent epigenetic effects were observed: (i) a very broad distribution of GFP intensities among cells in the GFP(+) population as well as individual GFP(+) clones and (ii) high-frequency GFP reporter gene silencing in GFP(-) cells. We previously showed that histone deacetylases (HDACs) can associate with ASV DNA soon after infection and may act to repress viral transcription at the level of chromatin. Consistent with this finding, we report here that treatment with the histone deacetylase inhibitor trichostatin A (TSA) induces GFP activation in GFP(-) cells and can also increase GFP expression in GFP(+) cells. In the case of the GFP(-) populations, we found that after removal of TSA, GFP silencing was reestablished in a subset of cells. We used that finding to enrich for stable GFP(-) cell populations in which viral GFP reporter expression could be reactivated by TSA; furthermore, we found that the ability to isolate such populations was independent of the promoter driving the GFP gene. In such enriched cultures, hCMV IE-driven, but not the viral long terminal repeat-driven, silent GFP reporter expression could be reactivated by the transcriptional activator prostratin. Microscopy-based studies using synchronized cells revealed variegated reactivation in cell clones, indicating that secondary epigenetic effects can restrict reactivation from silencing. Furthermore we found that entry into S phase was not required for reactivation. We conclude that HDACs can act rapidly to initiate and maintain promoter-independent retroviral epigenetic repression and silencing but that reactivation can be restricted by additional mechanisms.


Medicare Accountable Care Organizations and Antidepressant Use by Patients With Depression.
This study examined whether Medicare accountable care organization (ACO) programs were associated with early changes in antidepressant use or adherence among beneficiaries with depression. A difference-in-difference design was used to compare claims from Medicare fee-for-service beneficiaries (2009-2013) and ACO patients with those from local control groups. Outcome measures were total antidepressant days supplied, filling one or more antidepressant prescriptions, and proportion of days covered (PDC) by supply among antidepressant users (adherence). Among antidepressant users, ACO contracts were associated with slight differential increases in PDC (.4-.8 percentage point, p≤.03), depending on ACO program and entry year. The proportion of patients with one or more prescriptions was unchanged or decreased slightly for ACO patients with depression, such that total supply did not consistently increase. Medicare ACO programs were associated with early modest increases in antidepressant adherence but not with increases in the proportion of patients with depression who received antidepressants.


A Diagnostic Dilemma of Recurrent Disseminated Peritoneal Leiomyomatosis with Hypertrophied Omental Vessels: Imaging and Embolization of Omental Branches with Positive Outcome.
We present a case report of recurrent disseminated peritoneal leiomyomatosis in a 30-year-old female with a past history of laparoscopic myomectomy by a technique of morcellation for a large fibroid in 2014. After one year she presented in 2015 with a well-defined oval shaped fibroid along the anterior abdominal wall, which was supplied by the 10th intercostal artery and a branch of right internal mammary artery. She was again presented after 1 year in 2016 with a large pelvic-abdominal fibroid with blood supply from the omental artery, a branch from the right gastroepiploic artery, and sigmoid branches of inferior mesenteric artery.


Is the road to burnout paved with perfectionism? The prevalence of obsessive-compulsive personality disorder in a clinical longitudinal sample of female patients with stress-related exhaustion.
Few studies have investigated the relationship between stress-related mental health problems and obsessive-compulsive personality disorder (OCPD). Similarly, little research has focused on the moderating effect of OCPD on recovery in clinical patients with stress-related mental health problems. The general aim of this study was to investigate the prevalence of OCPD and the associations between OCPD and level of burnout, anxiety, and depression symptoms, during a 7-years follow-up in a clinical longitudinal sample of female patients with stress-related exhaustion. The included patients (n = 84) were referred to a specialist outpatient clinic for patients with stress-related exhaustion between 2006 and 2011. Data was collected at the initial examination and during a 7-year treatment follow-up. OCPD was the most common personality disorder in the present clinical sample, with 40% of patients fulfilling the criteria. There was a significant association between OCPD and the degree of burnout symptoms as well as the degree of depression, both at baseline and during the 7-year follow-up. No significant association between OCPD and levels of anxiety was observed. The results support the hypothesis that there might be an association between OCPD and stress-related exhaustion, including preservation of symptoms over time. OCPD and its related traits, such as perfectionism, may be important factors to consider when constructing effective treatment and rehabilitation plans for these patients.


Chronic intestinal psuedo-obstruction and MIDD, a rare cause of acute abdomen: implications in emergency surgery.
Chronic intestinal pseudo-obstruction (CIPO) is a condition typified by the failure of the small bowel to propel contents in the absence of physical obstruction. CIPO is diagnosed after eliminating other causes, presenting a diagnostic challenge in emergency surgery. We report a case of a 32-year-old man with a rare mitochondrial disorder, Maternally inherited diabetes and deafness (MIDD), who presented to our hospital acutely unwell with peritonitis. Laparotomy revealed distended small bowel with no transition point, and turbid fluid with no macroscopic source. Postoperatively he had severe electrolyte and vitamin deficiencies. The diagnosis of CIPO leading to paralytic ileus and bacterial translocation was established and managed with aggressive electrolyte and vitamin replacement. He was discharged day 12 post operatively after a prolonged ileus with follow-up from a quaternary metabolic unit. We discuss here the challenges and gold standard in the emergency management of CIPO.


Electron microscopic characterization of nuclear egress in the sea urchin gastrula.
Nuclear egress, also referred to as nuclear envelope (NE) budding, is a process of transport in which vesicles containing molecular complexes or viral particles leave the nucleus through budding from the inner nuclear membrane (INM) to enter the perinuclear space. Following this event, the perinuclear vesicles (PNVs) fuse with the outer nuclear membrane (ONM), where they release their contents into the cytoplasm. Nuclear egress is thought to participate in many functions such as viral replication, cellular differentiation, and synaptic development. The molecular basis for nuclear egress is now beginning to be elucidated. Here, we observe in the sea urchin gastrula, using serial section transmission electron microscopy, strikingly abundant PNVs containing as yet unidentified granules that resemble the ribonucleoprotein complexes (RNPs) previously observed in similar types of PNVs. Some PNVs were observed in the process of fusion with the ONM where they appeared to release their contents into the cytoplasm. These vesicles were abundantly observed in all three presumptive germ layers. These findings indicate that nuclear egress is likely to be an important mechanism for nucleocytoplasmic transfer during sea urchin development. The sea urchin may be a useful model to characterize further and gain a better understanding of the process of nuclear egress.


Erythropoietin increases the motility of human bone marrow-multipotent stromal cells (hBM-MSCs) and enhances the production of neurotrophic factors from hBM-MSCs.
Cell therapy has been extensively studied as an approach to repair damage in nervous system diseases. Multipotent stromal cells [MSCs] are well known to have neuroprotective effects and neural differentiation potential. The ability to induce migration of MSCs near nervous system damage via direct transplantation or via intravenous injections and increase the secretion of neurotrophic factors from MSCs might improve our ability to repair damage to the nervous system through cell therapy. In the present study, we investigated whether recombinant human erythropoietin [rhEPO], known to have a hematopoietic effect, could increase the motility of human bone marrow [hBM]-MSCs and enhance production of neurotrophic factors from hBM-MSCs. Based on the results of our MTT assay, trypan blue staining, and bromodeoxyuridine ELISA, rhEPO treatment increases the viability of MSCs but not their proliferation. With a migration assay kit, we demonstrated that the motility of hBM-MSCs was enhanced in rhEPO-treated cells. Immunoblotting assays revealed increased expression of phospho-Akt, phospho-GSK-3beta, phospho-extracellular signal-regulated kinase (ERK), beta PAK-interacting exchange factor (PIX), CXCR4, phospho tyrosine kinase B (TrkB), and vascular endothelial growth factor receptor-2 [VEGFR-2] in rhEPO-treated cells. Reverse transcription-polymerase chain reaction and gelatin zymography demonstrated that rhEPO treatment induces MMP-2 mRNA level and activity. In the studies using ELISAs, we found that rhEPO could increase levels of stromal cell-derived factor-1alpha, VEGF, and brain-derived neurotrophic factors. These findings suggest that rhEPO can increase the viability and motility of hBM-MSCs by affecting various intracellular signals including Akt, ERK, beta-PIX, CXCR4, TrkB, VEGFR-2, and MMP-2 and can enhance the production of neurotrophic factors from hBM-MSCs.


[Arrhythmias in acute coronary heart disease].
Almost any arrhythmia can occur as a complication of an acute coronary event. Many of them are frequent, but ventricular arrhythmias are predominant; supraventricular arrhythmias and conduction disturbances are only briefly reviewed in this article. Ventricular arrhythmias are important not only if they occur during the acute phase of a myocardial infarction but also when they are an acute symptom of coronary artery disease in themselves without evidence of myocardial necrosis. This article deals with the pathogenesis of ventricular arrhythmias, the factors influencing arrhythmias, the concept of warning premature beats, and prophylaxis and therapy in hospital as well as in the prehospital phase. In hospitalized patients these arrhythmias usually can be treated without major difficulty, but in the prehospital phase a further reduction of mortality probably could be achieved by suitable measures.


Determination of drug interactions occurring with the metabolic pathways of irinotecan.
Irinotecan or CPT-11 [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] is a derivative of camptothecine used in the treatment of advanced colorectal cancer. It requires activation to SN-38 (7-ethyl-10-hydroxycamptothecine) by carboxylesterase. Irinotecan and SN-38 are detoxified through two major metabolic pathways: the first one leads to oxidative degradation compounds, APC [7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecine] and NPC [7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine], and involves cytochrome P450 (3A4 isoform); the second one leads to SN-38 glucuronide (SN-38G) and involves UDP-glucuronosyltransferase (UGT). Using human hepatic microsomes, we studied the interactions of 15 drugs of common use in colorectal cancer patients on these metabolic pathways. Only nifedipine had a significant effect on SN-38 formation, decreasing carboxylesterase activity by 50% at 100 microM and 35% at 10 microM. Three drugs had a significant effect on SN-38G formation: clonazepam increased UGT activity by 50% at 100 microM and 30% at 10 microM, and nifedipine and vinorelbine inhibited the activity by 65 and 55% at 100 microM, respectively, with no effect at 10 microM. Five drugs exerted a significant inhibition on SN-38 formation at 100 microM: clonazepam (70%), methylprednisolone (50%), nifedipine (80%), omeprazole (85%), and vinorelbine (100%). Only omeprazole and vinorelbine still exerted a significant inhibition at 10 microM (30 and 90%, respectively), whereas only vinorelbine had a significant effect at 2 and 0.5 microM (70 and 40%, respectively). In conclusion, potential clinical interactions with the metabolism of irinotecan are likely to be important for vinorelbine, which strongly inhibits irinotecan catabolism by CYP3A4 at clinically relevant concentrations, but not for the other drugs, which exert an effect at concentrations not achievable in patients.


Fornix-based versus limbus-based conjunctival flap in trabeculectomy: a quantitative evaluation of the evidence.
To evaluate the efficacy and tolerability of limbus-based (LBCF) compared with fornix-based conjunctival flaps (FBCF) for trabeculectomy in the treatment of patients with uncontrolled glaucoma. A comprehensive literature meta-analysis was performed according to the Cochrane Collaboration methodology to identify controlled clinical trials comparing LBCF with FBCF in trabeculectomy. The efficacy measures were the weighted mean differences (WMDs) for intraocular pressure reduction (IOPR), the reduction in glaucoma medications, and the relative risks (RRs) for success rates. Tolerability estimates were measured by RR for adverse events. The pooled effects were calculated using the random effects model. Sixteen controlled clinical trials meeting the predefined criteria were included in the meta-analysis. A total of 1,825 eyes from 1,392 patients with medically uncontrolled glaucoma were included. The WMD of the IOPR from baseline was 1.12 (95% CI: -0.88 to 3.12) when comparing LBCF with FBCF. LBCF was associated with numerically greater but non-significant IOP lowering efficacy than FBCF (P = 0.270). LBCF was comparable with FBCF in the reduction of glaucoma medication, with a WMD of 0.15 (-0.05 to 0.36) at the follow-up endpoint (P = 0.141). The pooled RR comparing LBCF with FBCF were 1.08 (0.94, 1.23) for the complete success rate and 1.01 (0.92, 1.10) for the qualified success rate. Rates of adverse events did not differ significantly between LBCF and FBCF. There is no significant difference in IOP lowering, number of glaucoma medications, or proportion of patients who reached the IOP target between LBCF and FBCF trabeculectomy. Both incision techniques may contribute equally to adverse events.


Intergenerational concordance in Adult Attachment Interviews with mothers, fathers and adolescent sons and subsequent adjustment of sons to military service.
The study examined: (1) the intergenerational concordance between parents and their adolescent sons using the Adult Attachment Interview (AAI) categories and state-of-mind scales; and (2) the contribution of parents' state of mind with respect to attachment to their sons' adjustment during a stressful separation, as well as the possibility that sons' AAI mediates the associations between parents' AAI and sons' adjustment. Eighty-eight adolescents and their parents were interviewed using the AAI during the son's senior year in high school. Approximately a year later, during the first phase of compulsory military service, the adolescents and their peers reported on the sons' adjustment. Results demonstrated AAI correspondence between mothers' (but not fathers) and sons' categories (autonomous versus non-autonomous) and associations between mothers', fathers' and sons' AAI state-of-mind scales. The adjustment of sons of non-autonomous mothers (in particular, preoccupied mothers) was inferior to the adjustment of others. Mothers' and fathers' state of mind scales were associated with sons' adjustment, but sons' AAI did not mediate this association. The uniqueness of adolescence, the importance of parents' state of mind and the differences between mothers and fathers are discussed.


Chemical Constituents from Apios americana and Their Inhibitory Activity on Tyrosinase.
The goal of this study was to identify phytochemicals with inhibitory activity against tyrosinase. Nine compounds 1-9 were isolated from the tubers of Apios americana. This is the first report of aromadendrin 5-methyl ether (1) being isolated from the Apios species. Among them, compounds 2 and 8 showed inhibitory activity toward tyrosinase. Based on a Dixon plot, the potential Ki values of competitive inhibitors 2 and 8 were calculated as 10.3 ± 0.8 µM and 44.2 ± 1.7 µM, respectively. An IC50 value of 13.2 ± 1.0 µM was calculated for the slow-binding inhibitor 2 after preincubation with tyrosinase. Additionally, the predicted binding sites between the receptor and ligand, as well as secondary structure changes, in the presence of 2 were examined by molecular simulation.


Multiple-dose methotrexate for pregnancy in a cesarean section scar. A case report.
Pregnancy developing in a cesarean section scar is a very rare but possibly life-threatening condition because of the risk of rupture and excessive hemorrhage. A woman with previous cesarean section had transvaginal sonography performed at 7 weeks of gestation that showed a gestational sac implanted in the anterior isthmus wall of the uterus with 3 mm of myometrium between the sac and bladder wall. A diagnosis of pregnancy in the cesarean section scar was made. The patient was asymptomatic, and her hemodynamic condition was stable. Two courses of multiple-dose systemic methotrexate-folinic acid (1 mg/kg methotrexate intramuscularly on days 1, 3, 5 and 7 with 0.1 mg/kg folinic acid intramuscularly on days 2, 4, 6 and 8) were given. The patient tolerated it and remained stable during treatment. The serum hCG dropped to < 5 IU/L on day 56. Treatment with methotrexate is a non-surgical option that can improve preservation of the uterus in patients who desire fertility. A multiple-dose regimen causes rapid interruption of the pregnancy. This is very important because the risk of rupture and hemorrhage directly correlates with the duration of the pregnancy.


Wandering spleen causing splenic flexure volvulus and obstruction.
A 48-year-old woman presented with symptoms of distal bowel obstruction. On examination she had abdominal distension and a lump in the left lumbar and iliac regions. X-ray revealed distension of the colon with dilated small bowel. Exploration revealed an enlarged ptotic spleen whose pedicle caused obstruction of the colon. There was concomitant partial volvulus of the splenic flexure around the splenic pedicle. The splenic vein was thrombosed. Splenectomy was performed.


Nanostructures, Linear Rheological Responses, and Tunable Mechanical Properties of Microphase-Separated Cellulose-graft-Diblock Bottlebrush Copolymer Elastomers.
A series of cellulose-graft-diblock bottlebrush copolymer elastomers (cellulose-graft-poly(n-butyl acrylate)-block-poly(methyl methacrylate) (Cell-g-PBA-b-PMMA)) with short side chains were synthesized via successive atom transfer radical polymerization (ATRP) to study the influence of varying compositions and lengths of the graft diblock side chains on microphase morphologies and properties. The microphase-separated morphologies from misaligned spheres to cylinders were observed by atomic force microscopy (AFM) and small-angle X-ray scattering (SAXS) measurements. These bottlebrush copolymer elastomers possessed thermal stability and enhanced mechanical properties because the PMMA outer block could self-assemble into hard microdomains, which served as physical cross-links. The viscoelastic responses of these bottlebrush copolymers within the linear viscoelastic (LVE) regime were carried out by the oscillatory shear rheology. The time-temperature superposition (tTs) principle was applied to construct the master curves of the dynamic moduli, and the sequential relaxation of dense bottlebrush copolymers with different PMMA hard outer block lengths was analyzed. The rheological behaviors in this work could be utilized to build up the connection of microstructures and properties for the application of these bottlebrush copolymers as high-performance thermoplastic elastomers.