Pharmacogenomics of Bucindolol in Atrial Fibrillation and Heart Failure.
We explore the pharmacogenomics of the beta-blocker bucindolol by discussing relevant beta-1 adrenergic receptor (ADRB1) polymorphisms and recent beta-blocker studies. Through this, we will understand how bucindolol may help patients with atrial fibrillation and heart failure with reduced ejection fraction (AF-HFrEF), which carries poor prognosis. Retrospective study of the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training trial revealed the interaction between the optimal beta-blocker dose and the ADRB1 Arg389 genotype for HFrEF clinical outcomes. Further, a combinatorial genotype analysis in the Beta-Blocker Evaluation of Survival Trial showed that the Arg389Arg genotype, but not the Gly carrier, was associated with 40% lower mortality risk with bucindolol. Finally, the AF-HFrEF subgroup with the ADRB1 Arg389Arg genotype had greater heart rate reduction and suggestion for mortality benefit. Therapeutic response to beta-blockers varies by beta-blocker mechanism, ADRB1 Arg389 genotype, and clinical setting (AF, HFrEF, AF-HFrEF). The ongoing trial A Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Toprol-XL for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure prospectively identifies AF-HFrEF patients with favorable genotype for bucindolol to prevent AF recurrence.


Conformation and intermolecular interactions of SA2 peptides self-assembled into vesicles.
Previously we have shown that the recombinantly produced SA2 amphiphilic oligopeptide (Ac-Ala-Ala-Val-Val-Leu-Leu-Leu-Trp-Glu-Glu-COOH) self-assembles into nanovesicles (van Hell et al. 2007). In this study, the intermolecular interactions that contribute to the formation of such peptide vesicles are examined. First, analysis of a 3-hydroxyflavone fluorescent probe inserted into the peptide assemblies demonstrated that the peptide self-assembly is based on hydrophobic clustering. The polarity of this hydrophobic microenvironment was comparable to that of negatively charged lipid bilayers. A substantial level of hydration at the hydrophilic-hydrophobic interface was detected, as was further confirmed by tryptophan fluorescence analysis. However, organic solvents such as acetonitrile, tetrahydrofuran, or ethanol could not disrupt SA2 oligopeptide vesicles, whereas these solvents fully disintegrated lipid vesicles. Instead, the SA2 assembly immediately disintegrated in hydrogen breaking solvents such dimethylsulfoxide and dimethylformamide, suggesting the involvement of additional intermolecular interactions via hydrogen bonding. Circular dichroism and Fourier transform infrared spectroscopy excluded well-defined patterns of intramolecular hydrogen bonding and indicated the polyproline type II as the dominant SA2 peptide conformation, which enables intermolecular hydrogen bonding. All-atom computational simulations were used to confirm the presence of such intermolecular hydrogen bonds and degrees of hydration. On the basis of the experimental and computational data presented, we propose a model of an interdigitated peptide assembly that involves intermolecular hydrogen bonding in addition to hydrophobic interactions that stabilize SA2 oligopeptide vesicles.


Band Alignment of the CdS/Cu2Zn(Sn1- xGe x)Se4 Heterointerface and Electronic Properties at the Cu2Zn(Sn1- xGe x)Se4 Surface: x = 0, 0.2, and 0.4.
The surface electronic properties of the light absorber and band alignment at the p/n heterointerface are key issues for high-performance heterojunction solar cells. We investigated the band alignment of the heterointerface between cadmium sulfide (CdS) and Ge-incorporated Cu2ZnSnSe4 (CZTGSe), with Ge/(Ge + Sn) ratios ( x) between 0 and 0.4, by X-ray photoelectron, ultraviolet, and inversed photoemission spectroscopies (XPS, UPS, and IPES, respectively). In particular, we used interface-induced band bending in order to determine the conduction band offset (CBO) and valence-band offset (VBO), which were calculated from the core-level shifts of each element in both the CdS overlayer and the CZTGSe bottom layer. Moreover, the surface electronic properties of CZTGSe were also investigated by laser-irradiated XPS. The CBO at the CdS/CZTGSe heterointerface decreased linearly, from +0.36 to +0.20 eV, as x was increased from 0 to 0.4; in contrast, the VBO at the CdS/CZTGSe heterointerface was independent of Ge content. Both UPS and IPES revealed that the Fermi level at the CZTGSe surface is located near the center of the band gap. The hole concentration at the CZTGSe surface was on the order of 1011 cm-3, which is much smaller than that of the bulk (∼1016 cm-3). We discuss the differences in hole deficiencies near the surface and in the bulk on the basis of laser-irradiated XPS and conclude that hole deficiencies are due to defects distributed near the surface with densities that are lower than in the bulk, and the Fermi level is not pinned at the CZTGSe surface.


"You're dealing with an emotionally charged individual...": an industry perspective on the challenges posed by medical tourists' informal caregiver-companions.
Patients engage in medical tourism when they privately obtain a medical care abroad. Previous research shows that many medical tourists travel abroad with friends and family members who provide support and assistance. Meanwhile, very little is known about this important stakeholder group, referred to here as caregiver-companions. In this article we examine the challenges that can be posed by caregiver-companions and the overall practice of informal caregiving in medical tourism from an industry perspective. Specifically, we report on the findings of interviews conducted with international patient coordinators (IPCs) who work at destination facilities. IPCs come into regular contact with caregiver-companions in their professional positions and thus are ideally suited to comment on trends they have observed among this stakeholder group as well as the challenges they can pose to medical tourists, health workers, and facilities. We conducted 20 semi-structured interviews with 21 IPCs from 16 different facilities across nine countries. Topics probed in the interviews included caregiver-companion roles, IPCs' and others' interaction with caregiver-companions, and potential health and safety risks posed to medical tourists and caregiver-companions. Thematic analysis of the verbatim transcripts was employed. Although most participants encouraged medical tourists to travel with a caregiver-companion, many challenges associated with caregiver-companions were identified. Three themes best characterize the challenges that emerged: (1) caregiver-companions require time, attention and resources; (2) caregiver-companions can disrupt the provision of quality care; and (3) caregiver-companions can be exposed to risks. IPCs pointed out that caregiver-companions may, for example, have a negative impact on the patient through cost of accompaniment or inadequate care provision. Caregiver-companions may also create unanticipated or extra work for IPCs, as additional clients and by ignoring established organizational rules, routines, and expectations. Furthermore, caregiver-companions may be susceptible to stresses and health and safety risks, which would further deteriorate their own abilities to offer the patient quality care. Although caregiver-companions can pose challenges to medical tourists, health workers, and medical tourism facilities, they can also assist in enhancing best care and offering meaningful support to medical tourists. If caregiver-companions are open to collaboration with IPCs, and particularly in the form of information sharing, then their experience abroad can be safer and less stressful for themselves and, by extension, for the accompanied patients and facility staff.


Unusual Presentation of Multisystemic Inflammatory Syndrome.
COVID-19 pneumonia in children presents with very mild symptoms through an entity of multisystem inflammatory syndrome and can result in a life-threatening hyperinflammatory condition, with involvement of at least four organ systems and a marked inflammatory state. We present an 18-year-old high school student who presented with a sore throat, macular rash, abdominal pain, diarrhea, fevers, and joint pains. He presented with acute kidney injury and confusion with multiple tests and was eventually diagnosed with multisystem inflammatory syndrome in children (MIS-C).


Genome-Wide Identification and Characterization of Gibberellic Acid-Stimulated Arabidopsis Gene Family in Pineapple (Ananas comosus).
The gibberellic acid-stimulated Arabidopsis (GASA) gene family plays a crucial role in growth, development, and stress response, and it is specific to plants. This gene family has been extensively studied in various plant species, and its functional role in pineapple has yet to be characterized. In this study, 15 AcGASA genes were identified in pineapple through a genome-wide scan and categorized into three major branches based on a phylogenetic tree. All AcGASA proteins share a common structural domain with 12 cysteine residues, but they exhibit slight variations in their physicochemical properties and motif composition. Predictions regarding subcellular localization suggest that AcGASA proteins are present in the cell membrane, Golgi apparatus, nucleus, and cell wall. An analysis of gene synteny indicated that both tandem and segmental repeats have a significant impact on the expansion of the AcGASA gene family. Our findings demonstrate the differing regulatory effects of these hormones (GA, NAA, IAA, MeJA, and ABA) on the AcGASA genes. We analyzed the expression profiles of GASA genes in different pineapple tissue parts, and the results indicated that AcGASA genes exhibit diverse expression patterns during the development of different plant tissues, particularly in the regulation of floral organ development. This study provides a comprehensive understanding of GASA family genes in pineapple. It serves as a valuable reference for future studies on the functional characterization of GASA genes in other perennial herbaceous plants.


Taylor Dispersion Analysis of Polysaccharides Using Backscattering Interferometry.
Taylor dispersion analysis (TDA) allows the determination of the molecular diffusion coefficient (D) or the hydrodynamic radius (Rh) of a solute from the peak broadening of a plug of solute in a laminar Poiseuille flow. The main limitation plaguing the broader applicability of TDA is the lack of a sensitive detection modality. UV absorption is typically used with TDA but is only suitable for UV-absorbing or derivatized compounds. In this work, we present a development of the TDA method for non-UV absorbing compounds by using a universal detector based on refractive index (RI) sensing with backscattering interferometry (BSI). BSI was interfaced to a capillary electrophoresis-UV instrument using a polyimide coated fused silica capillary and an in-house designed flow-cell assembly. Polysaccharides were selected to demonstrate the application of TDA-BSI for size characterization. Under the conditions of validity of TDA, D and Rh average values and the entire Rh distributions were obtained from the (poly)saccharide taylorgrams, including non-UV absorbing polymers.


Insights into Amyotrophic Lateral Sclerosis from a Machine Learning Perspective.
Objective: Amyotrophic lateral sclerosis (ALS) disease state prediction usually assumes linear progression and uses a classifier evaluated by its accuracy. Since disease progression is not linear, and the accuracy measurement cannot tell large from small prediction errors, we dispense with the linearity assumption and apply ordinal classification that accounts for error severity. In addition, we identify the most influential variables in predicting and explaining the disease. Furthermore, in contrast to conventional modeling of the patient's total functionality, we also model separate patient functionalities (e.g., in walking or speaking). Methods: Using data from 3772 patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we introduce and train ordinal classifiers to predict patients' disease state in their last clinic visit, while accounting differently for different error severities. We use feature-selection methods and the classifiers themselves to determine the most influential variables in predicting the disease from demographic, clinical, and laboratory data collected in either the first, last, or both clinic visits, and the Bayesian network classifier to identify interrelations among these variables and their relations with the disease state. We apply these methods to model each of the patient functionalities. Results: We show the error distribution in ALS state prediction and demonstrate that ordinal classifiers outperform classifiers that do not account for error severity. We identify clinical and lab test variables influential to prediction of different ALS functionalities and their interrelations, and specific value combinations of these variables that occur more frequently in patients with severe deterioration than in patients with mild deterioration and vice versa. Conclusions: Ordinal classification of ALS state is superior to conventional classification. Identification of influential ALS variables and their interrelations help explain disease mechanism. Modeling of patient functionalities separately allows relation of variables and their connections to different aspects of the disease as may be expressed in different body segments.


Stacked autoencoders for unsupervised feature learning and multiple organ detection in a pilot study using 4D patient data.
Medical image analysis remains a challenging application area for artificial intelligence. When applying machine learning, obtaining ground-truth labels for supervised learning is more difficult than in many more common applications of machine learning. This is especially so for datasets with abnormalities, as tissue types and the shapes of the organs in these datasets differ widely. However, organ detection in such an abnormal dataset may have many promising potential real-world applications, such as automatic diagnosis, automated radiotherapy planning, and medical image retrieval, where new multimodal medical images provide more information about the imaged tissues for diagnosis. Here, we test the application of deep learning methods to organ identification in magnetic resonance medical images, with visual and temporal hierarchical features learned to categorize object classes from an unlabeled multimodal DCE-MRI dataset so that only a weakly supervised training is required for a classifier. A probabilistic patch-based method was employed for multiple organ detection, with the features learned from the deep learning model. This shows the potential of the deep learning model for application to medical images, despite the difficulty of obtaining libraries of correctly labeled training datasets and despite the intrinsic abnormalities present in patient datasets.


Depth of submucosal invasion does not predict lymph node metastasis and survival of patients with esophageal carcinoma.
There is controversy over the outcomes of esophageal adenocarcinoma with superficial submucosal invasion. We evaluated the impact of depth of submucosal invasion on the presence of metastatic lymphadenopathy and survival in patients with esophageal adenocarcinoma. Pathology reports of esophagectomy samples collected from 1997 to 2007 were reviewed. Specimens from patients with esophageal adenocarcinoma and submucosal invasion were reviewed and classified as superficial (upper 1 third, sm1) or deep (middle third, sm2 or deepest third, sm3) invasion. Outcomes studied were presence of metastatic lymphadenopathy and overall survival. Variables of interest were analyzed as factors that affect overall and cancer-free survival using Cox proportional hazards modeling. A multivariate model was constructed to establish independent associations with survival. The study included 80 patients; 31 (39%) had sm1 carcinoma, 23 (29%) had sm2 carcinoma, and 26 (33%) had sm3 carcinoma. Superficial and deep submucosal invasion were associated with substantial rates of metastatic lymphadenopathy (12.9% and 20.4%, respectively). The mean follow-up time was 40.5 +/- 4 months and the mean overall unadjusted survival time was 53.8 +/- 4.1 months. Factors significantly associated with reduced survival time included the presence of metastatic lymph nodes (hazard ratio [HR], 2.89; confidence interval [CI], 1.13-6.88) and esophageal cancer recurrence (HR 6.39, CI 2.40-16.14), but not depth of submucosal invasion. Patients with sm1 esophageal carcinoma have substantial rates of metastatic lymphadenopathy. Endoscopic treatment of superficial submucosal adenocarcinoma is not advised for patients that are candidates for surgery.


Concomitant chemo-radiotherapy in the treatment of locally advanced and/or metastatic soft tissue sarcomas: experience of the National Cancer Institute of Genoa.
Previous in vitro and in vivo studies showed a synergistic effect of concomitant doxorubicin and radiotherapy in a variety of solid tumors. From 1988 to 2000, we have investigated in a pilot study and then in a phase II study the efficacy of a concomitant doxorubicin radiotherapy treatment in patients with advanced and/or metastatic soft tissue sarcomas (STS). We enrolled and treated a group of 115 patients with advanced STS, with metastases (61%), frequently pretreated (59%), predominantly G2/G3 (84%). Doxorubicin was administered by continuous infusion at a dose of 12 mg/m(2)/day over 5 consecutive days concomitantly with radiotherapy; treatment was given on ambulatory basis at 2-week intervals with support of granulocytes colony stimulating factors (GCSF). In the whole group of 115 patients a clinical objective response (ORs) rate of 67% was obtained, with 11% complete and 56% partial responses. No patient progressed while on therapy, except one who progressed in non-irradiated metastatic tumor. Treatment (median 3 cycles) was well tolerated with no WHO grade 3 toxicity (apart from alopecia) and no acute or chronic cardiotoxicity. Thirty-nine responder patients underwent surgery (24 primary tumors, 10 relapses, 5 relapses plus isolated lung metastases). The median survival time(s) was 29 months in the whole series and over 50 months in responder patients. A multivariate analysis showed a positive association between survival and sex (HR=1.8; CI 95%, 1.0-3.4), performance status (HR=2.1; CI 95%, 1.1-4.0), ORs (HR=7.9; CI 95%, 3.5-18.1) and surgery (HR=8.8; CI 95%, 2.1-35.9). Low toxicity, high OR rate and positive survival time trend make the concomitant chemo-radiotherapy an efficacious approach for advanced STS.


18F-fluorodeoxyglucose uptake on positron emission tomography as a prognostic predictor in locally advanced hepatocellular carcinoma.
Metabolic activity assessed by (18)F-fluorodeoxyglocuse-positron emission tomography ((18)F-FDG-PET) reflects biological aggressiveness and prognoses in various tumors. The authors present a correlation between tumor metabolic activity and clinical outcomes in patients with hepatocellular carcinoma (HCC). Over a 3-year period (2005-2008), 135 locally advanced HCC patients were treated with localized concurrent chemoradiotherapy (CCRT; external beam radiotherapy at 45 grays for 5 weeks plus concurrent hepatic arterial infusion of 5-fluorouracil during the first and fifth week) followed by repetitive hepatic arterial infusional chemotherapy with 5-fluorouracil and cisplatin. Among them, the authors studied 107 who received (18)F-FDG-PET before CCRT. Maximal standardized uptake values (SUVs) of tumors were calculated. The median maximal tumor SUV was 6.1 (range, 2.4-∼19.2). Patients with low maximal tumor SUVs (<6.1) had a higher disease control rate than those with high maximal tumor SUVs (≥6.1) (86.8% vs 68.5%, respectively, P = .023). Both median progression-free survival (PFS; 8.4 vs 5.2 months; P = .003) and overall survival (OS; 17.9 vs 11.3 months; P = .013) were significantly longer in the low maximal tumor SUV group than in the high maximal tumor SUV group, respectively. In multivariate analysis, low maximal tumor SUV and objective responses to CCRT remained significant for PFS and OS. The high maximal tumor SUV group was more likely to have extrahepatic metastasis within 6 months than the low maximal tumor SUV group (58.1% vs 26.8%, respectively; P < .001). Similar results were obtained for the maximal tumor SUV/normal liver maximal SUV ratio (<2 vs ≥2) concerning progression, death, and extrahepatic metastasis. Metabolic activity may be useful not only in predicting prognosis and treatment responses, but also in establishing optimal treatment plans in locally advanced HCC.


Long-term follow-up of cervical cancer incidence after normal cytological findings.
An increase in cervical cancer incidence in Sweden from 2014 to 2015 has been attributed to an increase in false-negative cytological findings before cancer diagnoses. Years later, we performed a long-term follow-up to investigate whether the problem persisted. At each calendar year from 2016 to 2020, we identified women with prior normal cervical screening results through linkage to the Swedish National Cervical Screening Registry. We reported their incidence rates (IRs) of invasive cervical cancer in consecutive years and compared the IRs over time. For the years 2016 to 2020, there was no overall change in cervical cancer incidence after two normal cytology in the last two screening intervals. However, there was a further 62% increase among women 50 to 60 years of age with normal cytology in the past two screening intervals. The incidence rate of cervical cancer was high among nonscreened women and low among HPV-screened women with negative results, with no trends over time. Our results imply that the previously reported decrease in sensitivity of cervical cytology is persisting. Although primary cytology screening is no longer used, cytology is used in triaging among HPV-positive women. Our findings suggest that improved triaging is needed, for example, improved quality assurance and/or use of alternative triage tests.


High dietary fat intake during lactation promotes development of diet-induced obesity in male offspring of mice.
The maternal nutritional status during pregnancy and lactation influences the risk of obesity in offspring, but the details of this phenomenon are unclear. In particular, there is little information on the influence on the offspring of the maternal nutritional status during lactation only. Therefore, in this study, we examined the influence of high dietary fat intake in dams during lactation on the risk of obesity in offspring, using C57BL/6J mice. The mice were fed a control diet (CD) during pregnancy. After birth, dams were fed a CD or a high-fat diet (HD) during lactation (3 wk). Fat and energy were significantly increased in milk from dams fed a HD during lactation. Male offspring were weaned at 3 wk old and fed a CD for 4 wk, which resulted in no significant difference in their physique. Four weeks after weaning, the offspring (7 wk old) were fed a CD or HD for 4 wk to induce obesity. High dietary fat intake in dams and offspring promoted lipid accumulation in white adipose tissue and adipocyte hypertrophy in male offspring. The underlying mechanism may involve an increase in expression of Lpl and a decrease in expression of Hsl in white adipose tissue of offspring. In conclusion, our results show that high dietary fat intake during lactation promotes development of diet-induced obesity in male offspring.


Rational design of β-sheet ligands against Aβ42-induced toxicity.
A β-sheet-binding scaffold was equipped with long-range chemical groups for tertiary contacts toward specific regions of the Alzheimer's Aβ fibril. The new constructs contain a trimeric aminopyrazole carboxylic acid, elongated with a C-terminal binding site, whose influence on the aggregation behavior of the Aβ(42) peptide was studied. MD simulations after trimer docking to the anchor point (F19/F20) suggest distinct groups of complex structures each of which featured additional specific interactions with characteristic Aβ regions. Members of each group also displayed a characteristic pattern in their antiaggregational behavior toward Aβ. Specifically, remote lipophilic moieties such as a dodecyl, cyclohexyl, or LPFFD fragment can form dispersive interactions with the nonpolar cluster of amino acids between I31 and V36. They were shown to strongly reduce Thioflavine T (ThT) fluorescence and protect cells from Aβ lesions (MTT viability assays). Surprisingly, very thick fibrils and a high β-sheet content were detected in transmission electron microscopy (TEM) and CD spectroscopic experiments. On the other hand, distant single or multiple lysines which interact with the ladder of stacked E22 residues found in Aβ fibrils completely dissolve existing β-sheets (ThT, CD) and lead to unstructured, nontoxic material (TEM, MTT). Finally, the triethyleneglycol spacer between heterocyclic β-sheet ligand and appendix was found to play an active role in destabilizing the turn of the U-shaped protofilament. Fluorescence correlation spectroscopy (FCS) and sedimentation velocity analysis (SVA) provided experimental evidence for some smaller benign aggregates of very thin, delicate structure (TEM, MTT). A detailed investigation by dynamic light scattering (DLS) and other methods proved that none of the new ligands acts as a colloid. The evolving picture for the disaggregation mechanism by these new hybrid ligands implies transformation of well-ordered fibrils into less structured aggregates with a high molecular weight. In the few cases where fibrillar components remain, these display a significantly altered morphology and have lost their acute cellular toxicity.


[Perioperative management of non-deferrable oncologic surgeries during COVID-19 pandemic in Madrid, Spain. Is it safe?]
Surgical treatment during COVID-19 pandemic is controversial. Currently, most clinical guidelines advise to defer surgical patients during the COVID-19 pandemic, although the supporting data is sparse. We assumed that a COVID-19-free hospital, on the back of strong isolation measures and targeted screening, could reduce complications and enable us to continue treating high-risk patients. Prospective study with retrospective analysis of 355 patients who had undergone nondeferrable oncological surgery between March 16th, 2020, and April 14th, 2020, at our institution. The aim of the study was to assess the hospital restructuring and surgical protocols to be able to safely handle non-deferrable surgeries during the first wave of the COVID-19 pandemic. We implemented structural changes and an updated surgical-anesthetic protocol in order to isolate COVID-19 patients from other surgical patients. Comprehensive targeted screening for COVID-19 patients was made. PCR tests were requested for suspected COVID-19 patients. We analyzed mortality and complications related to both surgery and COVID-19 during hospital admission and also 15 and 30 days after surgery. We compared it with a sample of similar patients in the pre-pandemic period. Of the 355 patients enrolled in our study, 21 were removed due to COVID-19 infection, leaving a total of 334 patients in our final analysis. Post-operative complications were found in 37 patients (11.07%). Two patients died after surgery (0.6%). At the end of the study, COVID-19-related adverse outcomes were detected in six patients (1.79%). When comparing the complications of our original sample with the complications that occurred in the pre-COVID era, we found no statistically significant differences. Our results show that the surgical treatment of oncologic patients during the COVID-19 pandemic is safe, as long as the hospital performs surgeries under strict isolation measures and a robust screening method. It is necessary to select COVID-19 free hospitals for this matter in this and future pandemics.


A general strategy to develop fluorogenic polymethine dyes for bioimaging.
Fluorescence imaging is an invaluable tool to study biological processes and further progress depends on the development of advanced fluorogenic probes that reach intracellular targets and label them with high specificity. Excellent fluorogenic rhodamine dyes have been reported, but they often require long and low-yielding syntheses, and are spectrally limited to the visible range. Here we present a general strategy to transform polymethine compounds into fluorogenic dyes using an intramolecular ring-closure approach. We illustrate the generality of this method by creating both spontaneously blinking and no-wash, turn-on polymethine dyes with emissions across the visible and near-infrared spectrum. These probes are compatible with self-labelling proteins and small-molecule targeting ligands, and can be combined with rhodamine-based dyes for multicolour and fluorescence lifetime multiplexing imaging. This strategy provides access to bright, fluorogenic dyes that emit at wavelengths that are more red-shifted compared with those of existing rhodamine-based dyes.


[One aspect of training aircraft crews].
This paper describes the psychophysical training of crewmembers of flying vehicles who may find it necessary to cross a water boundary or to remain for long in water after emergency splash-down. In order to prevent attacks of fear and panic caused by such frightful things as whirlpools and convulsions the paper presents data on the nature of turbulent processes in running water and the techniques of overcoming them as well as on the origin of convulsions in swimmers and methods of their alleviation. The paper also describes an easy method of how to have a rest when swimming that makes it possible to eliminate the feeling of fatigue by remaining motionless for an infinitely long time.


Pseudopseudohypoparathyroidism and spinal cord compression.
A 42 year old Greek male with pseudo-pseudohypoparathyroidism presented with difficulty in walking and with lower limb weakness. His physical signs included short stature, thick neck, short fourth metacarpals and metatarsals, and a spastic paraparesis. Serum calcium and phosphate and parathyroid concentrations were normal. Myelography demonstrated compression of the cervical and lumbar cord in association with local bony abnormalities.


[Specificity of Tn9 insertion into the genome of bacteriophage lambda att80 depending on its preceding location].
It was shown that the site of previous integration (the donor site) of Tn9 affects the specificity of its next integration into the target molecule--phage lambda att80 DNA. The transposon integration sites were mapped by restriction and heteroduplex analysis following Tn9 transposition from chromosomal sites of Escherichia coli K-12 differing in location and Tn9 stability. When transposed from chromosomal galT::IS1 gene, Tn9 inserted into the site with coordinates 44,5 +/- 2 kb of lambda att80; when transposed from chromosomal attTn9A site, the transposon inserted into the sites with coordinates 31 +/- 0,7 kb or 33,3 +/- 0,5 kb. In the course of transposition of Tn9 from chromosomal attTn9N site the transposon inserted into the lambda att80 site with coordinates 26,5 +/- 5 kb. In the latter case, the increase of Tn9 single-stranded loop and the appearance of two new HindIII cleavage sites were observed in heteroduplex experiments. The data were interpreted as indicating structural rearrangements of Tn9 or linked sequences in the course of transposition.


Quantitative determination of amphetamine-type stimulants in sewage and urine by hybrid monolithic column solid-phase microextraction coupled with UPLC-QTRAP MS/MS.
A needle-solid-phase microextraction (SPME) method based on hybrid monolithic column (HMC) was proposed for simultaneous separation and extraction of seven amphetamine-type stimulants (ATSs) (amphetamine, methamphetamine, cathinone, methcathinone, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, and 3,4-methylenedioxyethylamphetamine), combining with ultra-performance liquid chromatography-triple quadrupole/linear ion trap mass spectrometer (UPLC-QTRAP MS/MS). Thiol functionalized HMC (T-HMC) showed high extraction efficiency and excellent elution results towards target analytes, among three kinds of single/bi-functionalized HMCs. Various parameters of SPME operation and analytical performance were investigated systematically. The adsorption mechanism of T-HMC to ATSs was also discussed and explained as a mixed mode of electrostatic and hydrophobic interactions. Under the optimum experimental conditions, the proposed T-HMC needle-SPME-UPLC-QTRAP MS/MS method was rapid and convenient with good accuracy, low sample consumption, high sensitivity and strong anti-interference ability. This method was successfully applied to quantitative determination of seven trace ATSs in complex sewage and urine samples. In view of abundant types of HMCs, the needle-SPME based on functional HMC also had the potential to selectively separating and enriching other tract new psychoactive substances in complex matrices, and could provide a reliable tool for drug monitoring, especially in applications for forensic analysis and drug abuse.


Processing LHC data in the UK.
The Large Hadron Collider (LHC) is one of the greatest scientific endeavours to date. The construction of the collider itself and the experiments that collect data from it represent a huge investment, both financially and in terms of human effort, in our hope to understand the way the Universe works at a deeper level. Yet the volumes of data produced are so large that they cannot be analysed at any single computing centre. Instead, the experiments have all adopted distributed computing models based on the LHC Computing Grid. Without the correct functioning of this grid infrastructure the experiments would not be able to understand the data that they have collected. Within the UK, the Grid infrastructure needed by the experiments is provided by the GridPP project. We report on the operations, performance and contributions made to the experiments by the GridPP project during the years of 2010 and 2011--the first two significant years of the running of the LHC.


Perceived family and individual social status and its association with depression and suicidality in an adolescent clinical sample.
There is a well-documented association between subjective social status (SSS) and depression among adults. Yet, the research on SSS and suicidal thoughts and behaviors among adolescent minority populations is limited. The aim of this study was to examine the relationship between the adolescent's SSS and mental health in an adolescent sample. A total of 197 adolescents ages 12 to 18 years (M age = 14.58; SD = 1.54) and their parents were recruited in urban outpatient clinics. Sociodemographics and measures of depression, suicidal thoughts and behaviors, and SSS were collected in a cross-sectional survey and through chart review. Univariate and multivariate analyses were conducted to calculate statistical associations with depression and suicidal thoughts and behaviors. Significant negative associations were found between SSS and depression, suicidal ideation, and prior suicidal attempts, independent of socioeconomic status. Consideration should be given to assessing measures of social rank to appraise risk in adolescent outpatient clinical settings.


Mechanisms of inflammasome activation: recent advances and novel insights.
Inflammasomes are cytosolic multiprotein platforms assembled in response to invading pathogens and other danger signals. Typically inflammasome complexes contain a sensor protein, an adaptor protein, and a zymogen - procaspase-1. Formation of inflammasome assembly results in processing of inactive procaspase-1 into an active cysteine-protease enzyme, caspase-1, which subsequently activates the proinflammatory cytokines, interleukins IL-1β and IL-18, and induces pyroptosis, a highly-pyrogenic inflammatory form of cell death. Studies over the past year have unveiled exciting new players and regulatory pathways that are involved in traditional inflammasome signaling, some of them even challenging the existing dogma. This review outlines these new insights in inflammasome research and discusses areas that warrant further exploration.


Development and application of a method for the analysis of 9 mycotoxins in maize by HPLC-MS/MS.
A reliable and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of aflatoxins (AFB1 , AFB2 , AFG1 , and AFG2 ), ochratoxin A (OTA), deoxynivalenol (DON), zearalenone (ZEA), fumonisin B1 (FB1 ), and T2-toxin in maize. The samples were first extracted using acetonitrile: water: acetic acid (79 : 20 : 1), and then further cleaned-up using OASIS HLB cartridge. Optimum conditions for the extraction and chromatographic separation were investigated. The mean recoveries of mycotoxins in spiked maize ranged from 68.3% to 94.3%. Limits of detection and quantification ranged from 0.01 to 0.64 μg/kg and from 0.03 to 2.12 μg/kg, respectively. The LC-MS/MS method has also been successfully applied to 60 maize samples, which were collected from Shaanxi Province of China. Twenty-four of the total 60 samples (40%) were contaminated with at least 1 of these 9 mycotoxins. Occurrence of mycotoxins were 6.7%, 1.7%, 3.3%, 6.7%, 1.7%, 23.3%, and 3.3% for AFB1 , AFB2 , OTA, ZEA, DON, FB1 , and T2-toxin, respectively. The results demonstrated that the procedure was suitable for the simultaneous determination of these mycotoxins in maize matrix.


Nurses' experiences of making decisions to call emergency assistance to their patients.
Patient survival often depends on decisions by nurses to call emergency assistance. The experiences of nurses calling emergency assistance have not been described. This descriptive study explored the experiences of registered nurses (n=32) using unstructured interviews. The main findings were that nurses questioned whether they were doing the 'right thing' calling the emergency team, sometimes collaborated with others prior to calling and most felt nervous and anxious. They recognized patient deterioration from feelings they had that something was wrong. However, they were not able 'to put their finger on it'. Knowing the patient and past experiences were involved in the recognition of deterioration. This association indicates the importance of experience in the development of clinical decision-making skills. Further, nurses calling emergency assistance need to be provided with the opportunity to debrief after calling. Their heavy reliance on subjective data before searching for objective data as outlined in the emergency calling criteria suggests that it is essential that nurses do not devalue or ignore concerns they may have about patients.


The impact of tumor necrosis factor α inhibitors on radiographic progression in ankylosing spondylitis.
To study the effect of tumor necrosis factor α (TNFα) inhibitors on progressive spinal damage in patients with ankylosing spondylitis (AS). All AS patients meeting the modified New York criteria who had been monitored prospectively and had at least 2 sets of spinal radiographs a minimum of 1.5 years apart were included in the study (n=334). The patients received standard therapy, which included nonsteroidal antiinflammatory drugs and TNFα inhibitors. Radiographic severity was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of AS progression that was ≥1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNFα inhibitors on the change in the mSASSS with varying followup periods. Potential confounders, such as disease activity (as assessed by the Bath Ankylosing Spondylitis Disease Activity Index), the erythrocyte sedimentation rate, C-reactive protein level, HLA-B27 positivity, sex, age at onset, smoking burden (number of pack-years), and baseline damage, were included in the model. TNFα inhibitor treatment was associated with a 50% reduction in the odds of progression, with an odds ratio (OR) of 0.52 (95% confidence interval [95% CI] 0.30-0.88, P=0.02). Patients with a delay of >10 years in starting therapy were more likely to experience progression as compared to those who started earlier (OR 2.4 [95% CI 1.09-5.3], P=0.03). In the ZINB model, the use of TNFα inhibitors significantly reduced disease progression when the gap between radiographs was >3.9 years. The protective effect of TNFα inhibitors was stronger after propensity score matching. Treatment with TNFα inhibitors appears to reduce radiographic progression in AS patients, especially with early initiation and with longer duration of followup.


Robust mutant strain design by pessimistic optimization.
Flux Balance Analysis (FBA) based mathematical modeling enables in silico prediction of systems behavior for genome-scale metabolic networks. Computational methods have been derived in the FBA framework to solve bi-level optimization for deriving "optimal" mutant microbial strains with targeted biochemical overproduction. The common inherent assumption of these methods is that the surviving mutants will always cooperate with the engineering objective by overproducing the maximum desired biochemicals. However, it has been shown that this optimistic assumption may not be valid in practice. We study the validity and robustness of existing bi-level methods for strain optimization under uncertainty and non-cooperative environment. More importantly, we propose new pessimistic optimization formulations: P-ROOM and P-OptKnock, aiming to derive robust mutants with the desired overproduction under two different mutant cell survival models: (1) ROOM assuming mutants have the minimum changes in reaction fluxes from wild-type flux values, and (2) the one considered by OptKnock maximizing the biomass production yield. When optimizing for desired overproduction, our pessimistic formulations derive more robust mutant strains by considering the uncertainty of the cell survival models at the inner level and the cooperation between the outer- and inner-level decision makers. For both P-ROOM and P-OptKnock, by converting multi-level formulations into single-level Mixed Integer Programming (MIP) problems based on the strong duality theorem, we can derive exact optimal solutions that are highly scalable with large networks. Our robust formulations P-ROOM and P-OptKnock are tested with a small E. coli core metabolic network and a large-scale E. coli iAF1260 network. We demonstrate that the original bi-level formulations (ROOM and OptKnock) derive mutants that may not achieve the predicted overproduction under uncertainty and non-cooperative environment. The knockouts obtained by the proposed pessimistic formulations yield higher chemical production rates than those by the optimistic formulations. Moreover, with higher uncertainty levels, both cellular models under pessimistic approaches produce the same mutant strains. In this paper, we propose a new pessimistic optimization framework for mutant strain design. Our pessimistic strain optimization methods produce more robust solutions regardless of the inner-level mutant survival models, which is desired as the models for cell survival are often approximate to real-world systems. Such robust and reliable knockout strategies obtained by the pessimistic formulations would provide confidence for in-vivo experimental design of microbial mutants of interest.


Plasma klotho and mortality risk in older community-dwelling adults.
The aging-suppressor gene klotho encodes a single-pass transmembrane protein that in mice is known to extend life span when overexpressed and resemble accelerated aging when expression is disrupted. It is not known whether there is a relationship between plasma levels of secreted klotho protein and longevity in humans. We measured plasma klotho in 804 adults, greater than or equal to 65 years, in the InCHIANTI study, a longitudinal population-based study of aging in Tuscany, Italy. During 6 years of follow-up, 194 (24.1%) of the participants died. In a multivariate Cox proportional hazards model, adjusting for age, sex, education, body mass index, physical activity, total cholesterol, high-density lipoprotein cholesterol, cognition, 25-hydroxyvitamin D, parathyroid hormone, serum calcium, mean arterial pressure, and chronic diseases, participants in the lowest tertile of plasma klotho (<575 pg/mL) had an increased risk of death compared with participants in the highest tertile of plasma klotho (>763 pg/mL; hazards ratio 1.78, 95% confidence interval 1.20-2.63). In older community-dwelling adults, plasma klotho is an independent predictor of all-cause mortality. Further studies are needed to elucidate the potential biological mechanisms by which circulating klotho could affect longevity in humans.


Antibody responses are generated to immunodominant ELK/KLE-type motifs on the nonstructural-1 glycoprotein during live dengue virus infections in mice and humans: implications for diagnosis, pathogenesis, and vaccine design.
Antibodies generated to the purified dengue type 2 virus (D-2V) nonstructural-1 (NS1) protein in mice and rabbits were compared with those generated to this protein in congeneic (H-2 class II) mouse strains and humans after D-2V infections. Unlike the profiles observed with the rabbits, similar antibody reaction profiles were generated by mice and humans with severe D-2V disease (dengue hemorrhagic fever [DHF]/dengue shock syndrome [DSS]). Many of these epitopes contained the core acidic-hydrophobic-basic (tri-amino-acid; ELK-type) motifs present in the positive or negative orientations. Antibody responses generated to these ELK/KLE-type motifs and the epitope LX1 on this protein were influenced by class II molecules in mice during D-2V infections; but these antibodies cross-reacted with human fibrinogen and platelets, as implicated in DHF/DSS pathogenesis. The core LX1 epitope (113YSWKTWG119), identified by the dengue virus complex-specific monoclonal antibody (MAb) 3D1.4, was prepared so that it contained natural I-Ad-binding and ELK-type motifs. This AFLX1 peptide, which appropriately displayed the ELK-type and LX1 epitopes in solid-phase immunoassays, generated a similar, but lower, immunodominant anti-ELK-motif antibody reaction in I-Ad-positive mice, as generated in mice and humans during D-2V infections. These antibody responses were much stronger in the high-responding mouse strains and each of the DHF/DSS patients tested and may therefore account for the association of DHF/DSS resistance or susceptibility with particular class II molecules and autoantibodies, antibody-stimulating cytokines (e.g., interleukin-6), and complement product C3a being implicated in DHF/DSS pathogenesis. These results are likely to be important for the design of a safe vaccine against this viral disease and showed the AFLX1 peptide and MAb 3D1.4 to be valuable diagnostic reagents.


The relative contributions of the folds and caveolae to the surface membrane of frog skeletal muscle fibres at different sarcomere lengths.
The plasmalemmal area of striated muscle fibres is greater than the apparent surface area (A = circumference x length) because of variable folds and the invaginations of the caveolae and T-tubules. Freeze-fracture replicas of the surface membrane of sartorius and semitendinosus muscles from Rana pipiens have been used to determine the numbers and distribution of folds and caveolae at different sarcomere lengths. (1) The plasmalemma folds are variable in size and shape, but are always oriented perpendicular to the long axis of the fibre. The folds vary with stretch, being more prominent at short sarcomere lengths. The caveolae are elliptical invaginations of the plasmalemma which open to the outside by a narrow "neck" of approximately 20 nm. The caveolar lumen has an average long dimension of 81.6 +/- 11.7 nm and an average short dimension of 66.9 +/- 7.9 nm. The caveolar "necks" only can be seen in freeze-fracture replicas and these are distributed in two circumferential bands on either side of the Z-line, and in longitudinal bands separated by distances of 1-5 mum. In the sartorius muscle, at a sarcomere length of 2.8 mum, there is an average number of thirty-seven caveolae per square micrometer of fibre surface. (2) During passive stretch the opening of folds provides membrane for the necessary increase in surface area up to a sarcomere length of about 3.0 mum. This length is defined as the critical sarcomere length (Sc). The number of caveolae remains constant at all sarcomere lengths less than Sc and thus their "necks" have been used as membrane markers to determine the amount of folding at different sarcomere lengths. The membrane area contained in folds and caveolae is expressed as a fraction of the apparent surface area (A). For example, in the sartorius muscle, at a sarcomere length of 2.4 mum, the membrane area, excluding the T-tubules, is: A + 0.1A (folding) + 0.7A (caveolae) = 1.8A. (3) For stretch beyond Sc membrane is provided by the opening of caveolae. At a sarcomere length of about 8 mum all the caveolae are open and the fibres rupture with further stretch. (4) The relative contributions of folds and caveolae vary with sarcomere length in a way that is consistent with assumptions of constant volume and plasmalemma area. The maintenance of constant plasmalemma area, even after excessive stretch, suggests that the plasmalemma is relatively inelastic in this situation.


Adaptive Time Location Sampling for COMPASS, A SARS-COV-2 Prevalence Study in Fifteen Diverse Communities in The United States.
COVID-19 has placed a disproportionate burden on underserved racial and ethnic groups, community members working in essential industries, those living in areas of high population density, and those reliant on in-person services such as transportation. The goal of this study was to estimate the cross-sectional prevalence of SARS-CoV-2 (active SARS-CoV-2 or prior SARS-CoV-2 infection) in children and adults attending public venues in 15 socio-demographically diverse communities in the United States, and to develop a statistical design that could be rigorously implemented amidst unpredictable stay-at-home COVID-19 guidelines. We used time-location sampling with complex sampling involving stratification, clustering of units, and unequal probabilities of selection to recruit individuals from selected communities. We safely conducted informed consent, specimen collection, and face-to-face interviews outside of public venues immediately following recruitment. We developed an innovative sampling design that adapted to constraints such as closure of venues; changing infection hotspots; and uncertain policies. We updated both the sampling frame and the selection probabilities over time using information acquired from prior weeks. We created site-specific survey weights that adjusted sampling probabilities for nonresponse and calibrated to county-level margins on age and sex at birth. Although the study itself was specific to COVID-19, the strategies presented in this paper could serve as a case study that can be adapted for performing population-level inferences in similar settings and could help inform rapid and effective responses to future global public health challenges.


Knowledge is insufficient for self-care among heart failure patients with psychological distress.
We conducted a study to identify barriers to, and factors promoting, self-care among heart failure (HF) patients with higher or lower levels of knowledge. Baseline data from 612 patients with HF enrolled in the REMOTE-HF trial were analyzed. Using median splits on the HF Knowledge Scale and the European HF Self-Care Behavior Scale, patients were divided into four groups: (a) low knowledge and good self-care, (b) low knowledge and poor self-care, (c) high knowledge and good self-care, and (d) high knowledge and poor self-care. Characteristics of the groups were compared using ANOVA, Kruskal-Wallis tests, and chi-square tests, followed by pairwise tests with Bonferroni correction. Variables significant in the univariate analyses were evaluated as predictors of self-care using hierarchical multiple linear regression. The potential moderating effect of knowledge was tested with interaction terms. The four groups did not differ in sociodemographics or health literacy scores, but differed in New York Heart Association (NYHA) class, comorbidities, and scores on depression, anxiety, and perceived control. In post hoc pairwise tests, patients with high knowledge and poor self-care tended to have worse NYHA class, greater depression and anxiety, and lower levels of perceived control than others. In the multivariate analysis, knowledge, depressive symptoms, and perceived control were significant predictors of self-care, as was the interaction between knowledge and anxiety. Screening and treatment of depression and anxiety is important in improving self-care among HF patients. HF management programs need to include strategies for increasing patients' perceived control over their heart disease.


Image presentation. The nipple-areolar complex: a pictorial review of common and uncommon conditions.
The purpose of this presentation is to show the radiologic findings of normal variants and benign and malignant diseases that affect the nipple-areolar complex. We evaluated the imaging findings of nipple-areolar complex lesions, using multiple breast imaging modalities including mammography, sonography, galactography, contrast-enhanced magnetic resonance imaging (MRI), and positron emission tomography/computed tomography. Radiologic features of nipple-areolar complex lesions, including Montgomery tubercles, nipple inversion, benign calcifications, inflammation, duct dilatations, intraductal papillomas, fibroadenomas, neurofibromatosis, dermatosis of the nipple, and breast malignancy, have been illustrated. A clinical examination is essential and an appropriate imaging evaluation with multiple modalities is often necessary to accurately diagnose an underlying abnormality of the nipple-areolar complex. Given the limitations of conventional mammography, supplemental mammographic views often are needed, and sonography may be performed to further characterize a mammographic or clinical finding. Also, contrast-enhanced MRI may be useful for additional evaluation.


Effects of ohmic heating with different voltages on the quality and microbial diversity of cow milk during thermal treatment and subsequent cold storage.
Ohmic heating (OH), an innovative heating technology, presents potential applications in the pasteurization of liquid foods. Therefore, the study was conducted to evaluate the effect of OH at various voltage gradients (10 V/cm, 12.5 V/cm, and 15 V/cm) and water bath (WB) on microbial inactivation, physicochemical and sensory properties and microbial flora of pasteurized milk. Results indicated that OH with higher voltage could effectively inactivate microorganisms in milk, requiring less heating time and energy. Moreover, OH treatment at higher voltages could decelerate lipid oxidation and better maintain the sensory quality and essential amino acids content of milk. Additionally, all treatments significantly altered the microbial community, and during storage, the microbial community in milk treated with 10 V/cm and 12.5 V/cm OH remained relatively stable. OH treatments with voltage gradients exceeding 12.5 V/cm could effectively inactive microorganisms and maintain the quality attributes of milk.


Quality of life in diverse groups of midlife women: assessing the influence of menopause, health status and psychosocial and demographic factors.
This paper examines whether menopausal status is associated with global quality of life (QOL) among women aged 40-55 and whether this association varies by race/ethnicity. We further examine the contributions of other health-related and psychosocial factors to QOL and whether these associations vary by racial/ethnic group. Analyses are based on 13,874 women who participated in the multi-ethnic, multi-race study of mid-aged women called the Study of Women's Health Across the Nation (SWAN). Study participants completed a 15-min telephone or in-person interview that contained questions on a variety of health-related topics. Items of interest for these analyses include global QOL, menstrual history (to assess menopausal status), sociodemographics, health status, lifestyle, and psychosocial variables. Results showed that in unadjusted analyses, early perimenopausal women reported lower QOL compared with premenopausal women, but menopausal status was no longer associated with QOL when analyses were adjusted for other variables. In multivariable models, being married and having low levels of perceived stress were associated with better QOL across all racial/ethnic groups. While there were many consistencies across racial/ethnic groups, we also found that the nature of the associations between QOL and education, marital status, perceived stress and social support varied across racial/ethnic groups.


Pharmacotherapy of essential thrombocythemia.
The natural history of essential thrombocythemia is characterized by an increased incidence of thrombotic and hemorrhagic events and, in the long-term, a tendency for disease transformation to myelofibrosis or acute leukemia. Advanced age and a prior history of thrombosis are the major predictors of thrombotic complications. The aim of this study was to outline the current evidence and the authors' opinion regarding the clinical management of patients with essential thrombocythemia. The study reviewed the pertinent literature addressing the management options for essential thrombocythemia patients. Cytoreductive agents can reduce the rate of thrombotic events, but do not affect the overall survival or rate of disease transformation. Thus, a risk-adapted strategy is recommended for the management of patients with essential thrombocythemia. High-risk patients with essential thrombocythemia should be treated with cytoreductive therapy and low-dose aspirin. Hydroxycarbamide is the agent of choice in most patients: however, interferon-alpha is a reasonable alternative in young patients, pregnancy or those intolerant of hydroxycarbamide. Low-risk patients can be safely observed. The management of intermediate-risk patients needs to be individualized: however, low-dose aspirin can be used after excluding acquired von Willebrand's disease. In the future we await the role of molecularly targeted therapy with JAK2 inhibitors in high-risk essential thrombocythemia patients.


[Annual review of progress in research on chronic obstructive pulmonary disease(2022-2023)].
Chronic obstructive pulmonary disease (COPD) is the most common chronic airway disease, with a high prevalence and high disease burden. Clinical questions have driven advances in clinical research that continue to deepen our understanding of COPD. At the same time, new perspectives, evidence, and strategies have emerged. Studies since 2022 have increased knowledge of the impact of risk factors, such as low-to-moderate income and ambient ozone, on the prevalence of COPD. The effect of preterm birth on obstructive lung function deficits and COPD in the sixth decade of life was investigated for the first time. Screening studies for COPD in developed and low- and middle-income countries suggest the importance of tailoring screening strategies to local conditions. Developments in artificial intelligence provide a general framework for using machine-learning-based methods and medical record-based labels to improve disease prediction. New perspectives on endotypes/phenotypes and prognostic assessment of COPD were provided by lifetime spirometry patterns of obstruction and limitation, sensitisation to recombinant Aspergillus fumigatus allergens, airway-occluding mucus plugs and exacerbation history in COPD group A and B patients. Clinical trials focusing on inflammatory mediators, comorbidity treatment, non-pharmacological treatments, and environmental interventions shed light on some crucial and long-debated issues. Further research is needed for individualised diagnosis and treatment of COPD.


Vasoactive intestinal peptide inhibits the activation of murine fibroblasts and expression of interleukin 17 receptor C.
Acute respiratory distress syndrome (ARDS) is an acute, severe, and refractory pulmonary inflammation with high morbidity and mortality. Excessive activation of fibroblast during the fibroproliferative phase plays a pivotal role in the prognosis of ARDS. Our previous study demonstrated that the vasoactive intestinal peptide (VIP) is mediated by lentivirus attenuates lipopolysaccharide (LPS)-induced ARDS in a murine model, and VIP inhibits the release of interleukin-17A (IL-17A) from activation macrophages. However, the effects of VIP on the activation of murine fibroblast and expression of IL-17 receptor (IL-17R) in ARDS remain unclear. Here, a mouse model of ARDS was established by an intratracheal injection of LPS. We found that the gene expression of col3a1 and hydroxyproline contents in the lungs were significantly increased 24 h after LPS injection. IL-17RC rather than IL-17RA was increased in the lungs of mice with ARDS. In vitro, LPS activated NIH3T3 cells, which was suppressed by VIP in a dose-dependent manner. In detail, VIP reduced the hydroxyproline content and col3a1 messenger RNA induced by LPS in NIH3T3 cells, as well as the expression of α-smooth muscle actin. Furthermore, we found that VIP inhibited the expression of IL-17R in the lungs of mice with ARDS and NIH3T3 cells stimulated with LPS, which was partly inhibited by antagonists of protein kinase A and protein kinase C. Taken together, our results demonstrated that VIP inhibited the activation of fibroblast via downregulation of IL-17RC, which may contribute to the protective effects of VIP against ARDS in mice.


The relationship between disgust sensitivity, anxiety and obsessions.
Three hundred participants, including volunteers from an obsessional support group, filled in questionnaires relating to disgust sensitivity, health anxiety, anxiety, fear of death, fear of contamination and obsessionality as part of an investigation into the involvement of disgust sensitivity in types of obsessions. Overall, the data supported the hypothesis that a relationship does exist between disgust sensitivity and the targeted variables. A significant predictive relationship was found between disgust sensitivity and total scores on the obsessive compulsive inventory (OCI; Psychological Assessment 10 (1998) 206) for both frequency and distress of symptomatology. Disgust sensitivity scores were significantly related to health anxiety scores and general anxiety scores and to all the obsessional subscales, with the exception of hoarding. Additionally, multiple regression analyses revealed that disgust sensitivity may be more specifically related to washing compulsions: frequency of washing behaviour was best predicted by disgust sensitivity scores. Washing distress scores were best predicted by health anxiety scores, though disgust sensitivity entered in the second model. It is suggested that further research on the relationship between disgust sensitivity and obsessionality could be helpful in refining the theoretical understanding of obsessions.


Microtubules remodel actomyosin networks in Xenopus egg extracts via two mechanisms of F-actin transport.
Interactions between microtubules and filamentous actin (F-actin) are crucial for many cellular processes, including cell locomotion and cytokinesis, but are poorly understood. To define the basic principles governing microtubule/F-actin interactions, we used dual-wavelength digital fluorescence and fluorescent speckle microscopy to analyze microtubules and F-actin labeled with spectrally distinct fluorophores in interphase Xenopus egg extracts. In the absence of microtubules, networks of F-actin bundles zippered together or exhibited serpentine gliding along the coverslip. When microtubules were nucleated from Xenopus sperm centrosomes, they were released and translocated away from the aster center. In the presence of microtubules, F-actin exhibited two distinct, microtubule-dependent motilities: rapid ( approximately 250-300 nm/s) jerking and slow ( approximately 50 nm/s), straight gliding. Microtubules remodeled the F-actin network, as F-actin jerking caused centrifugal clearing of F-actin from around aster centers. F-actin jerking occurred when F-actin bound to motile microtubules powered by cytoplasmic dynein. F-actin straight gliding occurred when F-actin bundles translocated along the microtubule lattice. These interactions required Xenopus cytosolic factors. Localization of myosin-II to F-actin suggested it may power F-actin zippering, while localization of myosin-V on microtubules suggested it could mediate interactions between microtubules and F-actin. We examine current models for cytokinesis and cell motility in light of these findings.


Effects of intraduodenal lipid and protein on gut motility and hormone release, glycemia, appetite, and energy intake in lean men.
Intraduodenal lipid modulates gastrointestinal motility and hormone release and suppresses energy intake (EI) more than does intraduodenal glucose. Oral protein is the most satiating macronutrient and modulates postprandial glycemia; the comparative effects of intraduodenal protein and lipid and their combined effects are unclear. We investigated the effects of intraduodenal protein and lipid, alone or in combination, on antropyloroduodenal motility, gastrointestinal hormone release, glycemia, and EI. Twenty lean men were studied on 5 randomized, double-blind occasions. Antropyloroduodenal motility, cholecystokinin, glucagon-like peptide-1 (GLP-1), insulin, glucagon, blood glucose, appetite, and nausea were measured during 90-min isocaloric (3 kcal/min) intraduodenal infusions of lipid [pure lipid condition (L3)], protein [pure protein condition (P3)], a 2:1 combination of lipid and protein [2:1 lipid:protein condition (L2P1)], a 1:2 combination of lipid and protein [1:2 lipid:protein condition (L1P2)], or a control. Immediately after the infusion, EI from a buffet lunch was quantified. In comparison with the control, all nutrient infusions suppressed antral and duodenal and stimulated pyloric pressures (P < 0.05). Cholecystokinin and GLP-1 release and pyloric stimulation were lipid-load dependent (r ≥ 0.39, P < 0.01), insulin and glucagon releases were protein-load dependent (r = 0.83, P < 0.001), and normoglycemia was maintained. L3 but not P3 increased nausea (P < 0.05). Compared with the control, L3 and P3 but not L2P1 or L1P2 suppressed EI (P < 0.05) without major effects on appetite. In lean men, despite differing effects on gut function, intraduodenal lipid and protein produce comparable reductions in energy intake. The effects of lipid may be a result of nausea. Protein also regulates blood glucose by stimulating insulin and glucagon. In contrast, at the loads selected, lipid:protein combinations did not suppress energy intake, suggesting that a threshold load is required to elicit effects. This trial was registered at Australia and New Zealand Clinical Trial Registry (http://www.anzctr.org.au) as 12609000949280.


The perioperative management of pain from intracranial surgery.
Analgesic therapy following intracranial procedures remains a source of concern and controversy. Although opioids are the mainstay of the "balanced" general anesthetic techniques frequently used during intracranial procedures, neurosurgeons and others have been reluctant to administer opioid analgesics to patients following such procedures. This practice is supported by the concern that the sedation and miosis associated with opioid administration could mask the early signs of intracranial catastrophe, or even exacerbate it through decreased ventilatory drive, elevated arterial carbon dioxide levels, and increased cerebral blood flow. This reluctance to use opioids following intracranial surgery is enabled by decades of training and anecdote emphasizing that pain is minimal following these procedures. However, recent data suggests otherwise, and raises the question of how to provide safe and effective analgesia for these patients. Here, this data is reviewed along with the relevant pain pathways, analgesic drugs and techniques, and the available data on their use following intracranial surgery. Although pain following intracranial surgery appears to be more intense than initially believed, it is readily treated safely and effectively with techniques that have proven useful following other types of surgery, including patient-controlled administration of opioids. The use of multimodal analgesic therapy is emphasized not only for its effectiveness, but to reduce dosages and, therefore, side effects, primarily of the opioids, that could be of legitimate concern to physicians and affect the comfort of their patients.


Replication mechanisms of circular ssDNA plant viruses and their potential implication in viral gene expression regulation.
The replication of members of the two circular single-stranded DNA (ssDNA) virus families Geminiviridae and Nanoviridae, the only ssDNA viruses infecting plants, is believed to be processed by rolling-circle replication (RCR) and recombination-dependent replication (RDR) mechanisms. RCR is a ubiquitous replication mode for circular ssDNA viruses and involves a virus-encoded Replication-associated protein (Rep) which fulfills multiple functions in the replication mechanism. Two key genomic elements have been identified for RCR in Geminiviridae and Nanoviridae: (i) short iterative sequences called iterons which determine the specific recognition of the viral DNA by the Rep and (ii) a sequence enabling the formation of a stem-loop structure which contains a conserved motif and constitutes the origin of replication. In addition, studies in Geminiviridae provided evidence for a second replication mode, RDR, which has also been documented in some double-stranded DNA viruses. Here, we provide a synthesis of the current understanding of the two presumed replication modes of Geminiviridae and Nanoviridae, and we identify knowledge gaps and discuss the possibility that these replication mechanisms could regulate viral gene expression through modulation of gene copy number.


A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion.
Cytokines and various cellular stresses are known to activate c-Jun NH2-terminal kinase (JNK), which plays a role in conveying signals from the cytosol to the nucleus. Here we investigate the translocation and activation of JNK1 during ischemia and reperfusion in perfused rat heart. Ischemia induces the translocation of JNK1 from the cytosol fraction to the nuclear fraction in a time-dependent manner. Immunohistochemical observation also shows that JNK1 staining in the nucleus is enhanced after ischemia. During reperfusion after ischemia, further nuclear translocation of JNK1 is apparently inhibited. In contrast, JNK1 activity in the nuclear fraction does not increased during ischemia but increases significantly during reperfusion with a peak at 10 min of reperfusion. The activation of JNK1 is confirmed by the phosphorylation of endogenous c-Jun (Ser-73) with similar kinetics. The level of c-jun mRNA also increases during reperfusion but not during ischemia. Based on fractionation and immunohistochemical analyses, an upstream kinase for JNK1, SAPK/ERK kinase 1 (SEK1), is constantly present in both the nucleus and cytoplasm throughout ischemia and reperfusion, whereas an upstream kinase for mitogen-activated protein kinase, MAPK/ERK kinase 1, remains in the cytosol. Furthermore, phosphorylation at Thr-223 of SEK1, necessary for its activation, rapidly increases in the nuclear fraction during postischemic reperfusion. These findings demonstrate that JNK1 translocates to the nucleus during ischemia without activation and is then activated during reperfusion, probably by SEK1 in the nucleus.


Mirtazapine in Comorbid Major Depression and Alcohol Dependence: An Open-Label Trial.
OBJECTIVE: This was a first pilot study evaluating the acute phase (8-week) efficacy of the antidepressant medication mirtazapine for the treatment of depressive symptoms and drinking of subjects with comorbid major depressive disorder and alcohol dependence (MDD/AD). We hypothesized that mirtazapine would demonstrate within-group efficacy for the treatment of both depressive symptoms and drinking in these subjects. METHODS: We conducted a first open label study of the second generation antidepressant mirtazapine in 12 adult outpatient subjects with comorbid major depressive disorder/alcohol dependence. The pharmacological profile of that medication is unique among antidepressants, unrelated to tricyclics or selective serotonin reuptake inhibitors. RESULTS: Mirtazapine was well tolerated in this treatment population. Self-reported depressive symptoms decreased from 31.8 to 8.3 on the Beck Depression Inventory, a 74.0% decrease (p<0.001), and drinking decreased from 33.9 to 13.3 drinks per week, a 60.8% decrease (p<0.05). None of the subjects were employed full-time at baseline, but 9 of the 12 (75%) were employed full-time at end-of-study. CONCLUSIONS: These preliminary findings suggest efficacy for mirtazapine for treating both the depressive symptoms and excessive alcohol use of comorbid major depressive disorder and alcohol dependence. Double-blind studies are warranted to further clarify the efficacy of mirtazapine in this population.


Concentric radiofrequency arrays to increase the statistical power of resting-state maps in monkeys.
The close homology of monkeys and humans has increased the prevalence of non-human-primate models in functional MRI studies of brain connectivity. To improve upon the attainable resolution in functional MRI studies, a commensurate increase in the sensitivity of the radiofrequency receiver coil is required to avoid a reduction in the statistical power of the analysis. Most receive coils are comprised of multiple loops distributed equidistantly over a surface to produce spatially independent sensitivity profiles. A larger number of smaller elements will in turn provide a higher signal-to-noise ratio (SNR) over the same field of view. As the loops become physically smaller, noise originating from the sample is reduced relative to noise originating from the coil. In this coil-noise-dominated regime, coil elements can have overlapping sensitivity profiles, yet still possess only mildly correlated noise. In this manuscript, we demonstrate that inductively decoupled, concentric coil arrays can improve temporal SNR when operating in the coil-noise-dominated regime-in contrast to what is expected for the more ubiquitous sample-noise-dominated array. A small, thin, 7-channel flexible coil is developed and operated in conjunction with an existing whole-head monkey coil. The mean and maximum noise correlation between the two arrays was 5% and 23%, respectively. When the flex coil was placed over the sensorimotor cortex, the temporal SNR improved by up to 2.3-fold in the peripheral cortex and up to 1.3-fold at a 2- to 3-cm depth within the brain. When the flex coil was placed over the frontal eye fields, resting-state maps showed substantially elevated sensitivity to correlations in the prefrontal cortex (54%), supplementary eye fields (39%), and anterior cingulate cortex (41%). The concentric-coil topology provided a pragmatic and robust means to significantly improve local temporal SNR and the statistical power of functional connectivity maps.


Anterior eye development and ocular mesenchyme: new insights from mouse models and human diseases.
During development of the anterior eye segment, cells that originate from the surface epithelium or the neuroepithelium need to interact with mesenchymal cells, which predominantly originate from the neural crest. Failures of proper interaction result in a complex of developmental disorders such Peters' anomaly, Axenfeld-Rieger's syndrome or aniridia. Here we review the role of transcription factors that have been identified to be involved in the coordination of anterior eye development. Among these factors is PAX6, which is active in both epithelial and mesenchymal cells during ocular development, albeit at different doses and times. We propose that PAX6 is a key element that synchronizes the complex interaction of cell types of different origin, which are all needed for proper morphogenesis of the anterior eye. We discuss several molecular mechanisms that might explain the effects of haploinsufficiency of PAX6 and other transcription factors, and the broad variation of the resulting phenotypes.


Differences in eating behaviour, well-being and personality between mothers following baby-led vs. traditional weaning styles.
Baby-led weaning, where infants self-feed family foods in place of traditional spoon-feeding of purees, is continuing to grow in popularity. Evidence is emerging which suggests that the method may promote healthier eating behaviour and weight gain in children, but the research is in its infancy. One issue is the self-selecting nature of participants to the approach. Although those who follow a baby-led approach are known to have a higher education and more professional occupation, little is known about wider maternal characteristics, which might affect either adoption of or outcomes of the method. The aim of this study was to explore differences in maternal characteristics between those adopting a baby-led or traditional approach. Six hundred four mothers with an infant aged 6-12 months completed a questionnaire including a copy of the Dutch Eating Behaviour Questionnaire (DEBQ), Brief Symptom Inventory (BSI) (anxiety, obsessive-compulsive and depression scales) and Ten Item Personality Questionnaire (TIPQ) alongside details of weaning approach (baby-led vs. traditional). Mothers who adopted a baby-led weaning style scored significantly lower on restrained eating (DEBQ), anxiety and introversion (TIPQ) and anxiety and obsessive-compulsive symptoms (BSI). Mothers who currently adopt a baby-led approach are therefore significantly different in personality, eating behaviour and well-being characteristics compared with those adopting a traditional approach. These characteristics may affect likelihood of choosing a baby-led approach or indirectly affect outcomes for infants weaned using the approach. Further research exploring baby-led weaning in a wider population sample is needed.


Emotional distress regulation takes precedence over impulse control: if you feel bad, do it!
Why do people's impulse controls break down during emotional distress? Some theories propose that distress impairs one's motivation or one's ability to exert self-control, and some postulate self-destructive intentions arising from the moods. Contrary to those theories, Three experiments found that believing that one's bad mood was frozen (unchangeable) eliminated the tendency to eat fattening snacks (Experiment 1), seek immediate gratification (Experiment 2), and engage in frivolous procrastination (Experiment 3). The implication is that when people are upset, they indulge immediate impulses to make themselves feel better, which amounts to giving short-term affect regulation priority over other self-regulatory goals.


Lineage analysis of newly generated neurons in organotypic culture of rat hippocampus.
New neurons are continuously generated in the hippocampus at the subgranular zone of the dentate granule cell layer throughout life. However, the lineage of newly generated neurons is unknown in detail. Here, using a retrovirus vector encoding EGFP, we labeled proliferating cells in an organotypic slice culture of the postnatal hippocampus of rat, and tracked their descendents over a long period. At 28 days post-inoculation, the phenotypes of the cells were immunohistochemically identified using specific antibodies to cell-type markers such as HuC/D (pan-neuronal marker), GFAP (astrocyte marker), Prox1 (dentate granule cell marker) or NeuN (mature neuronal marker). We found that the cells were mostly GFAP-negative in the HuC/D-positive lineages. The EGFP-expressing cells were often untraceable shortly after cell division in the HuC/D-positive lineages. The postmitotic periods of these cells distributed between 2 and 14 days. For the lineages expressing both Prox1 and NeuN the newborn cells became untraceable in a similar period (2-10 days). It is suggested that the newly generated neurons differentiate to mature dentate granule cells in the slice culture once they have survived over this critical traceability period.


The 'ins and outs' of faecal microbiota transplant for recurrent Clostridium difficile diarrhoea at Wits Donald Gordon Medical Centre, Johannesburg, South Africa.
Clostridium difficile-associated diarrhoea (CDAD) is a potentially life-threatening condition that is becoming increasingly common. A persistent burden of this infectious illness has been demonstrated over the past 4 years at Wits Donald Gordon Medical Centre (WDGMC), Johannesburg, South Africa, through implementation of active surveillance of hospital-acquired infections as part of the infection prevention and control programme. Oral treatment with metronidazole or vancomycin is recommended, but there is a major problem with symptomatic recurrence after treatment. Replacement of normal flora by the administration of donor stool through colonoscopy or nasogastric/duodenal routes is becoming increasingly popular. To identify risk factors for the development of CDAD in patients referred for faecal microbiota transplant (FMT) and evaluate the safety of administration of donor stool as an outpatient procedure, including via the nasogastric route. A retrospective record review of patients with recurrent CDAD referred for FMT at WDGMC between 1 January 2012 and 31 December 2016 was conducted. Twenty-seven patients were identified, all of whom fulfilled the criteria for recurrent CDAD. One-third were aged >65 years, and the majority were female. The most common risk factors were prior exposure to antibiotics or proton-pump inhibitors and underlying inflammatory bowel disease. Three procedures were carried out as inpatients and 24 in the outpatient gastroenterology unit. At 4-week follow-up, all patients reported clinical resolution of their diarrhoea after a single treatment and there were no recurrences. The FMT procedure was associated with no morbidity (with particular reference to the risk of aspiration when administered via the nasogastric route) or mortality. This case series confirms that FMT is a safe and effective therapy for recurrent CDAD. In most cases it can be administered via the nasogastric route in the outpatient department. We propose that the recently published South African Gastroenterology Society guidelines be reviewed with regard to recommendations for the route of administration of FMT and hospital admission. Meticulous prescription practice by clinicians practising in hospitals and outpatient settings, with particular attention to antimicrobials and chronic medication, is urgently required to prevent this debilitating and potentially life-threatening condition.


Use of continuous positive airway pressure reduces airway reactivity in adults with asthma.
Asthma is characterised by airway hyperreactivity, which is primarily treated with β-adrenergic bronchodilators and anti-inflammatory agents. However, mechanical strain during breathing is an important modulator of airway responsiveness and we have previously demonstrated in animal models that continuous positive airway pressure (CPAP) resulted in lower in vivo airway reactivity. We now evaluated whether using nocturnal CPAP decreased airway reactivity in clinically-stable adults with asthma. Adults with stable asthma and normal spirometry used nocturnal CPAP (8-10 cmH(2)O) or sham treatment (0-2 cmH(2)O) for 7 days. Spirometry and bronchial challenges were obtained before and after treatment. The primary outcome was the provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC(20)). The CPAP group (n=16) had a significant decrease in airway reactivity (change in (Δ)logPC(20) 0.406, p<0.0017) while the sham group (n=9) had no significant change in airway reactivity (ΔlogPC(20) 0.003, p=0.9850). There was a significant difference in the change in airway reactivity for the CPAP versus the sham group (ΔlogPC(20) 0.41, p<0.043). Our findings indicate that chronic mechanical strain of the lungs produced using nocturnal CPAP for 7 days reduced airway reactivity in clinically stable asthmatics. Future studies of longer duration are required to determine whether CPAP can also decrease asthma symptoms and/or medication usage.


Photobiomodulation Enhances Cisplatin Cytotoxicity in a Culture Model with Oral Cell Lineages.
Cisplatin plays a central role in cancer chemotherapy, but resistance to this drug remains a major obstacle in treatment. Drawbacks related to cisplatin failure may be associated with cell energy metabolism. This study investigated whether photobiomodulation (PBM) can potentiate the effects of cisplatin on keratinocytes (HaCat) and cancer cells (SCC25 and HN12). Cells were treated with laser (GaAlAs; 660 nm; 60 mW; 0.33 J; 2.14 W cm-2 ; 11.7 J cm-2 and 6 s) and cisplatin (7.8 μg mL-1 ) to evaluate cell viability, Ki-67, VEGF, TGF-β1, EGF expression and ROS production. Observations were validated in the SCC25 cell lineage, where the type of cell death (necrosis/apoptosis) and the amount of ATP were assessed. Cell lineages showed increased sensitivity to cisplatin associated with PBM (Cis-PBM). Ki-67 was augmented in all cell lineages treated with Cis-PBM when compared to cisplatin alone (Cis). Cis or Cis-PBM significantly decreased VEGF expression in cancer cells, while no changes were seen in the expression of TGF-β1 or EGF compared to control. ROS levels were similar in the Cis and Cis-PBM groups. Cells treated with Cis-PBM died by apoptosis, leading to greater consumption of ATP. These observations suggest that PBM may potentiate the effects of cisplatin, leading to increased drug cytotoxicity and enhanced cell death.


Characterization of selectively 13C-labeled synthetic melittin and melittin analogues in isotropic solvents by circular dichroism, fluorescence, and NMR spectroscopy.
The spectroscopic and functional characterization of 13C-labeled synthetic melittin and three analogues is described. Selectively 13C-enriched tryptophan ( [13C delta 1]-L-Trp) and glycine ( [13C alpha]Gly) were incorporated into melittin and three analogues by de novo peptide synthesis. 13C-Labeled tryptophan was incorporated into melittin at position 19 and into single-tryptophan analogues of melittin at positions 17, 11, and 9, respectively. Each of the synthetic peptides contained 13C-labeled glycine at position 12 only. The peptides were characterized functionally in a cytolytic assay, and spectroscopically by CD, fluorescence, and NMR. The behavior of 13C-labeled synthetic melittin was, in all respects, indistinguishable from that of the naturally occurring peptide. All of the analogues were found to be efficient lytic agents and thus were functionally similar to the native peptide, yet no evidence was found for formation of a melittin-like tetramer by any of the analogues in aqueous media, although there was a propensity for apparently nonspecific peptide aggregation, especially for MLT-W9. Since the analogues did exhibit fractional helicities by CD comparable to or even greater than melittin itself in the presence of methanol, we infer that tetramer assembly requires not only the ability to form alpha-helix but also a very precise packing of amino acid side chains of the constituent monomers. The 13C chemical shift of the Gly-12 C alpha was found to be a sensitive marker for helix formation in all of the peptides. For melittin itself, 13C NMR spectra revealed a downfield shift of approximately 1.8 ppm for the Gly-12 13C alpha resonance of the tetramer relative to that observed for the free monomer in D2O. In mixed samples containing melittin monomer and tetramer, two discrete Gly-12 13C alpha peaks were observed simultaneously, suggestive of slow exchange between the two species. We conclude that melittin's ability to form a soluble tetramer is not a prerequisite for cytolytic activity, nor is cytolytic potential precisely correlated with the ability to form an amphiphilic helix.


[Pneumocystis carinii pneumonia in HIV infection. Diagnosis, prognostic factors and curative treatment].
The diagnosis of Pneumocystis carinii pneumonia (PCP) rests on the isolation of this micro-organism in patients whose latest blood count, less than 2 months old, shows less than 250 CD4 lymphocytes per cubic mm and who present with signs of impaired lung function. Bronchoalveolar lavage (BAL) is the reference diagnostic method, but induced expectoration may be the initial examination, in which case BAL is performed only when the latter fails or gives negative results. Prognostic factors are those of any interstitial pneumonia plus those specific to PCP and those associated with HIV infection. It is only when no initial severity factor is present that cure can be contemplated, provided the effectiveness of treatment is evaluated daily. Cotrimoxazole is the reference drug for comparisons with all new treatments; the indications of corticosteroid therapy and the necessity of intensive care techniques are now better determined. The frequency of PCP and its mortality rate should be reduced, and one may look forward to a time when this disease will be rare and atypical, thereby raising other diagnostic and therapeutic problems.


[Barrett esophagus and Barrett carcinoma].
The incidence of Barrett carcinoma has increased almost six-fold in the last 20 years. Barrett oesophagus is defined as the presence of metaplastic columnar epithelium in the oesophagus in continuity with the gastric mucosa. It is regarded as an acquired abnormality, developed as a result of chronic (duodenal) gastro-oesophageal reflux. It is especially the intestinal type of columnar epithelium that has a greatly enhanced risk of malignant degeneration. It is advisable that patients with a Barrett oesophagus should regularly be examined endoscopically, with extensive tissue biopsy. Presence of Barrett epithelium without dysplasia or with only moderate dysplasia does not in itself constitute an indication for supplementary treatment. Major dysplasia constitutes an indication for prophylactic resection. In the treatment with curative intention of Barrett carcinoma, surgery is the therapy of first choice.


Conversion during off-pump coronary artery bypass graft surgery: A case-control study.
Off pump coronary artery bypass (OPCAB) surgery is carried out as an alternative to conventional coronary artery bypass grafting using cardiopulmonary bypass (CPB). At times 'conversion' to CPB may be required to bail out a situation resulting from acute decompensation of the heart. It is reported that such conversion carries significant mortality risk. Since we conduct coronary revascularization by OPCAB technique as the preferred technique, we conducted this study with an aim to identify the markers of adverse outcome during conversion in Indian patients. Case control retrospective study. Tertiary referral center. We conducted three thousand two hundred OPAB surgeries in the period between 2013 to16. Ninety patients (3.1%) required conversion to complete the revascularization (Con version group). Twice the number of patients who underwent OPCAB surgery without conver sion were chosen as controls (Control group). OPCAB surgery Results: Mortality in the conversion group was 5.56% in contrast to 0.06% in the controls (P = 0.01). The conversion group had higher left ventricular end diastolic pressure, incidence of endarterectomy, and intra-aortic balloon counter pulsation requirement. Female gender was also predictive of conversion. The total chest drain, duration of ventilation, ICU stay and hospital stay were also higher in the conversion group. Conversion was associated with 9.47 times the odds for mortality. Conversion during OPCAB is associated with significantly increased mortality. Female gender, increased left ventricular end diastolic pressure and preoperative requirement of Intra-aortic balloon are markers of increased risk of mortality when converted.


Two novel dammarane-type compounds from the leaves and stems of Panax quinquefolium L.
Two new dammarane-type compounds were isolated from the leaves and stems of Panax quinquefolium L. The new compounds were named as pseudo-ginsenoside RT6 (1) and pseudoginsengenin R1 (2). The structures of the new compounds were elucidated by the combined analysis of NMR and HR-ESI-MS as (20S,24R)-6-O-β-d-glucopyranosyl-dammar-3-one-20,24-epoxy-6α,12β,25-triol (1) and (20S,24R)-dammar-3-one-20,24-epoxy-6α,12β,25-triol (2).


Transvaginal ultrasound versus magnetic resonance imaging for preoperative assessment of myometrial infiltration in patients with endometrial cancer: a systematic review and meta-analysis.
To compare the diagnostic accuracy of transvaginal ultrasound (TVS) and magnetic resonance imaging (MRI) for detecting myometrial infiltration (MI) in endometrial carcinoma. An extensive search of papers comparing TVS and MRI in assessing MI in endometrial cancer was performed in MEDLINE (PubMed), Web of Science, and Cochrane Database from January 1989 to January 2017. Quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Our extended search identified 747 citations but after exclusions we finally included in the meta-analysis 8 articles. The risk of bias for most studies was low for most 4 domains assessed in QUADAS-2. Overall, pooled estimated sensitivity and specificity for diagnosing deep MI were 75% (95% confidence interval [CI]=67%-82%) and 82% (95% CI=75%-93%) for TVS, and 83% (95% CI=76%-89%) and 82% (95% CI=72%-89%) for MRI, respectively. No statistical differences were found when comparing both methods (p=0.314). Heterogeneity was low for sensitivity and high for specificity for TVS and MRI. MRI showed a better sensitivity than TVS for detecting deep MI in women with endometrial cancer. However, the difference observed was not statistically significant.


Potassium deficiency triggers the development of dormant cells (akinetes) in Aphanizomenon ovalisporum (Nostocales, Cyanoprokaryota)(1).
Akinetes are spore-like nonmotile cells that differentiate from vegetative cells of filamentous cyanobacteria from the order Nostocales. They play a key role in the survival and distribution of these species and contribute to their perennial blooms. Various environmental factors were reported to trigger the differentiation of akinetes including light intensity and quality, temperature, and nutrient deficiency. Here, we report that deprivation of potassium ion (K(+) ) triggers akinete development in the cyanobacterium Aphanizomenon ovalisporum. Akinetes formation is initiated 3 d-7 d after an induction by K(+) depletion, followed by 2-3 weeks of a maturation process. Akinete formation occurs within a restricted matrix of environmental conditions such as temperature, light intensity or photon flux. Phosphate is essential for akinete maturation and P-limitation restricts the number of mature akinetes. DNA replication is essential for akinete maturation and akinete development is limited in the presence of Nalidixic acid. While our results unequivocally demonstrated the effect of K(+) deficiency on akinete formation in laboratory cultures of A. ovalisporum, this trigger did not cause Cylindrospermopsis raciborskii to produce akinetes. Anabaena crassa however, produced akinetes upon potassium deficiency, but the highest akinete concentration was achieved at conditions that supported vegetative growth. It is speculated that an unknown internal signal is associated with the cellular response to K(+) deficiency to induce the differentiation of a certain vegetative cell in a trichome into an akinete. A universal stress protein that functions as mediator in K(+) deficiency signal transduction cascade, may communicate between the lack of K(+) and akinete induction.


Treatment of bifurcation lesions with two stents: one year angiographic and clinical follow up of crush versus T stenting.
To compare long term outcomes of the crush versus the T technique in bifurcation lesions. 182 consecutive patients were identified who underwent percutaneous coronary interventions for bifurcation lesions with drug eluting stents between April 2002 and January 2004. Two techniques were used according to the operator's discretion: crush (group C, n = 121) or T (group T, n = 61). In-hospital outcome differed significantly between the two groups. Angiographic follow up was available for 142 (78%) patients. Groups C and T did not differ significantly regarding late loss (0.42 (0.39) mm v 0.34 (0.35) mm, p = 0.52) and rate of restenosis (16.2% v 13.0%, p = 0.80) in both the main and the side branch without final kissing balloon post-dilatation. However, when final kissing balloon post-dilatation was performed, group C had significantly lower late lumen loss (0.23 (0.21) mm v 0.37 (0.33) mm, p = 0.02) and restenosis rate (8.6% v 26.5%, p = 0.04) in the side branch. At one year's clinical follow up, group C compared with group T had lower rates of target lesion revascularisation (14.0% v 31.1%, p = 0.01) and target vessel revascularisation (16.5% v 32.8%, p = 0.02). In non-selected bifurcation lesions treated with drug eluting stents, the restenosis rate remains relatively high in the side branch. Compared with the T stenting technique, crush stenting with kissing balloon post-dilatation is associated with a reduced rate of restenosis in the side branch.