Effects of pirfenidone targeting the tumor microenvironment and tumor-stroma interaction as a novel treatment for non-small cell lung cancer.
Targeting cancer-associated fibroblasts (CAFs), as well as the crosstalk between stroma and cancer cells, could be of value in managing cancers. Pirfenidone (PFD) is an anti-fibrotic agent for idiopathic pulmonary fibrosis. This study aimed to investigate the possibility that PFD might exert an anti-tumor effect through inhibition of fibroblast activation and the tumor-stroma interaction in non-small cell lung cancer (NSCLC) cell lines in vitro and in vivo. PFD significantly inhibited myofibroblast differentiation and activation of both primary cultured normal human lung fibroblasts and CAFs. Cocultivation of NSCLC cells with conditioned media (CM) of fibroblasts changed the morphology or epithelial to mesenchymal transition (EMT) status, and PFD suppressed these changes. Cocultivation of CAFs with CM of NSCLC cells also induced activation of CAFs, and these changes were suppressed by PFD. On in vivo examination, CAFs promoted tumor progression, and PFD suppressed tumor progression with an inhibitory effect on tumor-stroma crosstalk. PFD might inhibit not only fibroblast activity, but also the crosstalk between cancer cells and fibroblasts. PFD may have great potential as a novel treatment for NSCLC from multiple perspectives.


Epsins and Vps27p/Hrs contain ubiquitin-binding domains that function in receptor endocytosis.
Ubiquitin functions as a signal for sorting cargo at multiple steps of the endocytic pathway and controls the activity of trans-acting components of the endocytic machinery (reviewed in refs 1, and 2). By contrast to proteasome degradation, which generally requires a polyubiquitin chain that is at least four subunits long, internalization and sorting of endocytic cargo at the late endosome are mediated by mono-ubiquitination. Here, we demonstrate that ubiquitin-interacting motifs (UIMs) found in epsins and Vps27p (ref. 9) from Saccharomyces cerevisiae are required for ubiquitin binding and protein transport. Epsin UIMs are important for the internalization of receptors into vesicles at the plasma membrane. Vps27p UIMs are necessary to sort biosynthetic and endocytic cargo into vesicles that bud into the lumen of a late endosomal compartment, the multivesicular body. We propose that mono-ubiquitin regulates internalization and endosomal sorting by interacting with modular ubiquitin-binding domains in core components of the protein transport machinery. UIM domains are found in a broad spectrum of proteins, consistent with the idea that mono-ubiquitin can function as a regulatory signal to control diverse biological activities.


Rosmarinic acid treatment during porcine oocyte maturation attenuates oxidative stress and improves subsequent embryo development in vitro.
In vitro maturation (IVM) of oocytes has been widely used in the field of assisted reproductive technology. However, oocytes can be injured by oxidative stress during the process of IVM. The present study was designed to evaluate the influences of rosmarinic acid (RA) on the IVM of porcine oocytes and the subsequent development of early-stage embryos as well as its underlying mechanisms. Various concentrations of RA (5 µM, 10 µM, and 25 µM) were treated with porcine oocyte maturation medium during the period of IVM. The results showed that 5 µM RA treatment during the period of porcine oocyte IVM improves blastocyst quality and hatching ability after parthenogenetic activation. Furthermore, the presence of RA during the period of IVM dramatically improved the total number of cells after somatic cell nuclear transfer compared to the number of cells in the control group. Notably, RA treatment during the period of porcine oocyte IVM decreased intracellular reactive oxygen species generation not only in oocytes but also in cumulus cells. Further analysis showed that the intracellular free thiols levels in the oocytes were enhanced by treatment with RA during the period of porcine oocyte IVM compared to the free thiols levels in the control groups. These results indicate that RA improves the developmental competence of porcine oocytes during the IVM period by attenuating oxidative stress.


[Endoscope-assisted thyroidectomy with minimal incision in neck].
To explore the feasibility of endoscope-assisted thyroidectomy with minimal neck incision. Endoscope-assisted thyroid surgeries had been accomplished through incision above sternal notch and in submental area respectively from August 2003 to August 2005, including 11 partial lobectomy, 3 lobectomy, 2 two-sides partial lobectomy, 1 isthmectomy. In this group, 12 cases approached through above sternal notch, 5 cases approached through the submental area, and all were successful. The mean length of incisions was 2.3 cm (range from 1.5 cm to 3.0 cm). No one was converted to open surgery. The mean time of operation was 61.3 minutes (range from 30 minutes to 120 minutes). The mean volume of hemorrhage during the operation was 15.6 ml (range from 10 to 40 ml). The mean volume of drainage of post-operation was 22.5 ml (range from 6 ml to 40 ml). The mean length of stay was 4. 5 days (range from 3 days to 6 days). There were no hoarseness and no low serum calcium. Following visits were performed after operation from 1 month to 12 months, and there were no stiff feelings on skin. The cosmetic outcomes of the incisions were good, except 1 case for scar physique. Endoscope-assisted thyroidectomy was safe and feasible with good cosmetic outcome. The selection of approach with minimal incision depends on the location of neoplasm.


Effect of hypohydration on gastric emptying and intestinal absorption during exercise.
Dehydration and hyperthermia may impair gastric emptying (GE) during exercise; the effect of these alterations on intestinal water flux (WF) is unknown. Thus the purpose of this study was to determine the effect of hypohydration ( approximately 2.7% body weight) on GE and WF of a water placebo (WP) during cycling exercise (85 min, 65% maximal oxygen uptake) in a cool environment (22 degrees C) and to also compare GE and WF of three carbohydrate-electrolyte solutions (CES) while the subjects were hypohydrated. GE and WF were determined simultaneously by a nasogastric tube placed in the gastric antrum and via a multilumen tube that spanned the duodenum and the first 25 cm of jejunum. Hypohydration was attained 12-16 h before experiments by low-intensity exercise in a hot (45 degrees C), humid (relative humidity 50%) environment. Seven healthy subjects (age 26.7 +/- 1.7 yr, maximal oxygen uptake 55.9 +/- 8.2 ml . kg-1 . min-1) ingested either WP or a 6% (330 mosmol), 8% (400 mosmol), or a 9% (590 mosmol) CES the morning following hypohydration. For comparison, subjects ingested WP after a euhydration protocol. Solutions ( approximately 2.0 liters total) were ingested as a large bolus (4.6 ml/kg body wt) 5 min before exercise and as small serial feedings (2.3 ml/kg body wt) every 10 min of exercise. Average GE rates were not different among conditions (P > 0.05). Mean (+/-SE) values for WF were also similar (P > 0.05) for the euhydration (15.3 +/- 1.7 ml . cm-1 . h-1) and hypohydration (18.3 +/- 2.6 ml . cm-1 . h-1) experiments. During exercise after hypohydration, water absorption was greater (P < 0.05) with ingestion of WP (18.3 +/- 2. 6) and the 6% CES (16.5 +/- 3.7), compared with the 8% CES (6.9 +/- 1.5) and the 9% CES (1.8 +/- 1.7). Mean values for final core temperature (38.6 +/- 0.1 degrees C), heart rate (152 +/- 1 beats/min), and change in plasma volume (-5.7 +/- 0.7%) were similar among experimental trials. We conclude that 1) hypohydration to approximately 3% body weight does not impair GE or fluid absorption during moderate exercise when ingesting WP, and 2) hyperosmolality (>400 mosmol) reduced WF in the proximal intestine.


Characterization and Quantification of Tryptophan- and Tyrosine-derived Hydroperoxides.
The reaction of singlet oxygen (1 O2 ) with the amino acids tryptophan and tyrosine, either free or inserted in peptides or proteins, gives rise to hydroperoxides. To understand the impact of these hydroperoxides in complex biological systems, methods allowing their characterization and accurate quantification must be available. In this work, hydroperoxides derived from tryptophan and tyrosine and from peptides containing these amino acids were synthesized by photooxidation, and characterized by high-resolution mass spectrometry. In addition, experiments were carried out to compare two colorimetric methods commonly used for quantification of peroxides, namely the iodometric and the ferric-xylenol orange assays. For the tryptophan hydroperoxide, the quantifications obtained by colorimetric methods were then compared to that obtained by NMR. The results showed that for the ferric-xylenol orange method, the stoichiometry between peroxide and Fe3+ ions varies considerably. On the other hand, for the iodometric assay, the stoichiometry peroxide:I3 - ions is always 1:1. However, the kinetics of the reactions of peroxides with I- vary, and the assay must be performed in anaerobic conditions. Thus, the iodometric method is more appropriate for precise quantification of a given peroxide. The characterization and accurate quantification of biological peroxides is key to understand the mechanisms involved in redox processes.


Evaluation of Situational Judgment Tests in student selection in Indonesia and the impact on diversity issues.
Internationally, medical selection relies heavily on prior academic attainment which has an adverse impact on the diversity of selected students. Since non-academic attributes are also important, this study aims to evaluate the use of a Situational Judgment Test (SJT) for selection and the impact on student diversity relating to gender, ethnicity and socio-economic status. Previous SJT research has almost entirely originated from a Western context and this study focuses on new evidence in a South East Asian context with a different demographic profile. Thirty faculty members developed 112 SJT scenarios assessing professionalism, communication and self-awareness domains. The scenarios underwent a concordance stage where stakeholder input was sought on the content appropriateness, to define the item scoring key, followed by an initial psychometric evaluation with first and second year medical students (N = 436). Based on these results, 30 scenarios, consisting of 128 nested items, were selected for pilot testing and evaluation regarding diversity issues with two cohorts of applicants in 2017 (N = 446) and 2018 (N = 508). The SJT demonstrated good internal consistency (Cronbach's alpha of 0.80 and 0.81 respectively). There were significant differences in SJT scores based on gender in both years, where females consistently outperformed males (p = .0001). However, no significant differences were found based on high school origin, parental educational background or ethnicity. This is the first study to evaluate the use of an SJT in Indonesia, which has a unique diversity profile compared to Western countries. Largely, the preliminary results replicate previous studies of the potential diversity benefits of using an SJT as a tool for medical student selection and has the potential to level the playing field regarding socio-economic status and ethnicity. Further studies exploring more variables representing diversity are warranted to confirm the early results in this study.


Pegylated liposomal doxorubicin in patients with metastatic triple-negative breast cancer: 8-year experience of a single center.
The known efficacy of doxorubicin in metastatic breast cancer is countered by its dose-limiting myelosuppression and cardiotoxicity. Pegylated liposomal doxorubicin (PLD) was discovered to overcome these problems. But the data regarding its use in metastatic TNBC (triple-negative breast cancer) is still insufficient. Our study aimed to assess the factors affecting the outcome of the patients with metastatic TNBC who received PLD. During a period of 8 years (January 2011-December 2018), we analyzed 39 eligible patients. The disease control rate (DCR) was 51.3%. Among all the analyzed factors, two of them significantly affected DCR. The first factor was the chemosensitivity to prior anthracycline. As patients with chemosensitive disease had higher DCR than those with the chemoresistant disease (P = .001). The second factor was the number of prior lines of chemotherapy. As the patients who received two prior lines had a higher DCR than those who received three lines or more (P = .023). Chemosensitivity was the only significant independent factor for DCR (odds ratio = .095, P = .008). For the studied patients, the median progression-free survival (PFS) was 7 months. The anthracycline-chemosensitivity was the only significant independent prognostic factor for PFS (P = .002). The median overall survival (OS) was 12 months. There was a marginally significant effect of anthracycline-chemosensitivity on OS (P = .052). The anthracycline-chemosensitivity is an independent predictive and prognostic factor for the patients with metastatic TNBC receiving PLD. In developing countries, PLD should be reserved for the patients whose tumors are anthracycline-chemosensitive.


Dual Level Adaptive Weighting for Cloth-Changing Person Re-Identification.
For the long-term person re-identification (ReID) task, pedestrians are likely to change clothes, which poses a key challenge in overcoming drastic appearance variations caused by these cloth changes. However, analyzing how cloth changes influence identity-invariant representation learning is difficult. In this context, varying cloth-changed samples are not adaptively utilized, and their effects on the resulting features are overshadowed. To address these limitations, this paper aims to estimate the effect of cloth-changing patterns at both the image and feature levels, presenting a Dual-Level Adaptive Weighting (DLAW) solution. Specifically, at the image level, we propose an adaptive mining strategy to locate the cloth-changed regions for each identity. This strategy highlights the informative areas that have undergone changes, enhancing robustness against cloth variations. At the feature level, we estimate the degree of cloth-changing by modeling the correlation of part-level features and re-weighting identity-invariant feature components. This further eliminates the effects of cloth variations at the semantic body part level. Extensive experiments demonstrate that our method achieves promising performance on several cloth-changing datasets. Code and models are available at https: //github.com/fountaindream/DLAW.


Antioxidative activity of new N-oxides of tertiary amines: membrane model and chromogen studies.
Potential antioxidative activities of three series of newly synthesized N-oxides were studied. Individual components in each of the series differed in the lipophilicities and number of free radical scavenging groups. Various methods were used to determine their antioxidative efficiencies: Prevention of erythrocyte membrane lipid oxidation induced by UV irradiation and chromogen experiments in which antioxidative efficiencies of compounds were compared to that of the standard antioxidant Trolox (a water-soluble vitamin E analogue). Additionally, some hemolytic (pig erythrocytes) and differential scanning calorimetry (DSC) measurements were performed to determine a mechanism of the interaction between membranes and N-oxides. It was found that N-oxides, especially those of long alkyl chains (> C12H25), readily interacted with both, erythrocyte and liposomal membranes. No marked differences were found in their protection of erythrocytes against oxidation. In most cases inhibition of oxidation changed between 15% and 25%. Still, it was far better than in chromogen experiments where suppression of free radicals reached 20% in the best case. It may be concluded that antioxidative capabilities of N-oxides are moderate. Studies on the interaction mechanism showed that incorporation of particular compounds into model membranes varied. Hemolysing activities of compounds increased with the elongation of the alkyl chain but differed for corresponding compounds of particular series indicating that lipophilicity of compounds is not the only factor determing their interaction with erythrocyte membranes. DSC experiments showed that N-oxides, upon incorporation into 1,2-dipalmitoyl-3-sn-phosphatidylcholine liposomes, shifted the subtransition (Tp) and the main transition (Tm). The shifts observed depended on the alkyl chain length. The effects differed for each series. It seems that in the case of long alkyl chain compounds the domain formation may take place. Generally, the decrease of Tm was greatest for the same compounds that exhibited the best hemolytic efficacy. The same conclusion concerns the decrease of cooperativity of the main transition and the observed changes suggest an increase in membrane fluidity. Both, erythrocyte and DSC experiments seem to indicate that compounds of particular series incorporate in a somewhat different way into membranes.


[Advances in combination strategies with oncolytic virotherapy].
Compared with conventional treatments, oncolytic virotherapy has the advantages of enhanced cytotoxicity, improved targeting, and minimal side effects. However, its efficacy is not as good as expected for the single drug treatment. The purpose of synergistic effect is one of the development directions of existing oncolytic virus therapy. In this paper, through a systematic review of the current preclinical and clinical trials progress of oncolytic virus combination therapy, the combined treatment strategies of oncolytic virus and immune checkpoint inhibitors, chemotherapy, targeted therapy,and cell therapy are reviewed to provide reference for further clinical application.


A systematic review of the amount and timing of light in association with objective and subjective sleep outcomes in community-dwelling adults.
Light is considered the dominant environmental cue, or zeitgeber, influencing the sleep-wake cycle. Despite recognizing the importance of light for our well-being, less is known about the specific conditions under which light is optimally associated with better sleep. Therefore, a systematic review was conducted to examine the association between the amount and timing of light exposure in relation to sleep outcomes in healthy, community-dwelling adults. A systematic search was conducted of four databases from database inception to June 2016. In total, 45 studies met the review eligibility criteria with generally high study quality excepting for the specification of eligibility criteria and the justification of sample size. The majority of studies involved experimental manipulation of light (n = 32) vs observational designs (n = 13). Broad trends emerged suggesting that (1) bright light (>1000 lux) has positive implications for objectively assessed sleep outcomes compared to dim (<100 lux) and moderate light (100-1000 lux) and (2) bright light (>1000 lux) has positive implications for subjectively assessed sleep outcomes compared to moderate light (100-1000 lux). Effects due to the amount of light are moderated by the timing of light exposure such that, for objectively assessed sleep outcomes, brighter morning and evening light exposure are consistent with a shift in the timing of the sleep period to earlier and later in the day, respectively. For subjectively assessed sleep outcomes, brighter light delivered in the morning was associated with self-reported sleep improvements and brighter evening light exposure was associated with worse self-reported sleep.


[Initial antiretroviral therapy in HIV-infected patients].
In 2014 an antiretroviral treatment should be initiated in any HIV-infected patient, whatever his/her CD4 lymphocyte count. The objectives of antiretroviral treatment are both individual (restoration or preservation of immune functions, decreased morbidity and mortality, decreased chronic systemic inflammation) and collective (decreased risk of HIV sexual transmission). Preferred initial regimens include two nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine) plus a third agent, either a non-nucleoside reverse transcriptase inhibitor (rilpivirine or efavirenz), or a ritonavir-boosted protease inhibitor (atazanavir or darunavir). Alternatively, the third agent may be chosen among integrase inhibitors (raltegravir, dolutegravir, elvitegravir/cobicistat). Immunologic and virologic response to first-line antiretroviral therapy should be monitored closely according to specific criteria and objectives.


Production of recombinant porin from Y. pseudotuberculosis in a water-soluble form for pseudotuberculosis diagnostics.
OmpF porin from the outer membrane of Yersinia pseudotuberculosis was cloned into pET-40b(+) plasmid. Using E. coli Rosetta (DE3) strain, MX medium, IPTG concentration of 0.2 mm and post-induction cultivation at 14°C overnight allowed us to obtain a water-soluble form of the recombinant protein (rs-OmpF). Rs-OmpF was shown to have the ordered spatial structure at the levels of secondary and tertiary structure. Rs-OmpF was found to be effective as diagnostic antigen in ELISA for pseudotuberculosis diagnostics.


Ontogeny and sexual dimorphism of the sonic motor nucleus in the oyster toadfish.
Male oyster toadfish, Opsanus tau, produce a courtship boatwhistle call and have a larger sound-producing organ than females, who do not boatwhistle . We investigated the possibility of sexual dimorphism in ontogeny of the sonic motor nucleus (SMN) of the toadfish. Brain weight increases for life though the increase decelerates with increasing fish weight. Neuron number, ranging from 760 to 2,888 in the SMN, increases rapidly to about 3 years, more slowly to about 8 years, and then levels off. There are no sexual differences in regressions of brain weight and SMN neuron number against fish size or age. Neuronal soma size in the SMN increases from 8 to 35 micron in average diameter and 67 to 916 micron2 in area over a period of at least 7 years. Males have larger neurons than females (P less than .01). However, males can be separated by inspection into populations with large and small soma sizes. Neuron size is not different between females and males with small somas. Neurons in males with large somas are larger than neurons in females and neurons in males with small somas. Such male dimorphism is reminiscent of other behavioral and morphological dimorphisms , which have led to characterization of males into territorial and satellite forms in certain mating systems.


Prostate and Bladder Cancer Coexistence in Patients Undergoing Radical Cystoprostatectomy.
According to the Polish National Cancer Registry, bladder cancer is the 4th most common cancer in the male population (7.0%), while prostate cancer takes 2nd place (14.0%). In the case of both cancer types, prognoses are precarious and depend on many factors, such as the size of the primary tumor, infiltration of regional lymph nodes, histological grade and occurrence of distant metastases. The objective of this work is to verify the coincidence of prostate cancer and bladder cancer in patients who underwent radical cystoprostatectomy in Wroclaw Medical University, Department of Urology and Oncological Urology, as well as to indicate factors that may influence the peri- and post-operative course. We have retrospectively reviewed patients who underwent radical cystoprostatectomy for muscular-invasive bladder cancer between 2009 and 2014, which comprised of 116 male patients. We managed to establish telephone and personal contact with the patients. Seventeen of the 116 patients were diagnosed with coincidental prostate cancer in post-operative histological examination (14.6%). This result is lower than in other series of cystoprostatectomy cases (range 23-68%). The mean age of patient was 68.9 years and the median was 69.5 years. Factors influencing the peri- and post-operative periods were not statistically significant. Serum PSA level and DRE should be performed more often on patients prepared for radical cystoprostatectomy. An accurate pre-operative assessment of cancer infiltration is required for both types of tumors. Complete resection of prostate prevents residual neoplasm infiltration. It is important to take into account the possibility of primary prostate tumor occurrence in patients qualified for radical cystectomy. The post-operative supervision should be focused not only on bladder carcinoma but on the prostate carcinoma, too.


The molecular mechanism by which saturated lysophosphatidylcholine attenuates the metastatic capacity of melanoma cells.
Lysophophatidylcholine (LysoPC) is an abundant constituent in human plasma. Patients with malignant cancer diseases have attenuated LysoPC plasma levels, and thus LysoPC has been examined as a metabolic biomarker for cancer prediction. Preclinical studies have shown that solid tumor cells drastically degrade LysoPCs by incorporating their free fatty acids into cell membrane phospholipids. In this way, LysoPC C18:0 reduced the metastatic spread of murine melanoma B16.F10 cells in mice. Although membrane rigidification may have a key role in the attenuation of metastasis, evidence for this has yet to be shown. Therefore, the present study aimed to determine how LysoPC reduces the metastatic capacity of B16.F10 cells. Following cellular preincubation with LysoPC C18:0 at increasing concentrations and lengths of time, cell migration was most significantly attenuated with 450 μm LysoPC C18:0 at 72 h. Biosensor measurements suggest that, despite their abundance in B16.F10 cells, LysoPC-sensitive G protein-coupled receptors do not appear to contribute to this effect. Instead, the attenuated migration appears to result from changes in cell membrane properties and their effect on underlying signaling pathways, most likely the formation of focal adhesion complexes. Treatment with 450 μm LysoPC C18:0 activates protein kinase C (PKC)δ to phosphorylate syndecan-4, accompanied by deactivation of PKCα. Subsequently, focal adhesion complex formation was attenuated, as confirmed by the reduced activity of focal adhesion kinase (FAK). Interestingly, 450 μm LysoPC C18:1 did not affect FAK activity, explaining its lower propensity to affect migration and metastasis. Therefore, membrane rigidification by LysoPC C18:0 appears to prevent the formation of focal adhesion complexes, thus affecting integrin activity as a key for metastatic melanoma spread.


Neutron Scattering Analysis of Water's Glass Transition and Micropore Collapse in Amorphous Solid Water.
The question of the nature of water's glass transition has continued to be disputed over many years. Here we use slow heating scans (0.4 K min^{-1}) of compact amorphous solid water deposited at 77 K and an analysis of the accompanying changes in the small-angle neutron scattering signal, to study mesoscale changes in the ice network topology. From the data we infer the onset of rotational diffusion at 115 K, a sudden switchover from nondiffusive motion and enthalpy relaxation of the network at <121 K to diffusive motion across sample grains and sudden pore collapse at >121 K, in excellent agreement with the glass transition onset deduced from heat capacity and dielectric measurements. This indicates that water's glass transition is linked with long-range transport of water molecules on the time scale of minutes and, thus, clarifies its nature. Furthermore, the slow heating rates combined with the high crystallization resistance of the amorphous sample allow us to identify the glass transition end point at 136 K, which is well separated from the crystallization onset at 144 K-in contrast to all earlier experiments in the field.


Lorentz invariance with an invariant energy scale.
We propose a modification of special relativity in which a physical energy, which may be the Planck energy, joins the speed of light as an invariant, in spite of a complete relativity of inertial frames and agreement with Einstein's theory at low energies. This is accomplished by a nonlinear modification of the action of the Lorentz group on momentum space, generated by adding a dilatation to each boost in such a way that the Planck energy remains invariant. The associated algebra has unmodified structure constants. We also discuss the resulting modifications of field theory and suggest a modification of the equivalence principle which determines how the new theory is embedded in general relativity.


Computed Tomography-Guided Interstitial Brachytherapy for Locally Advanced Cervical Cancer: Introduction of the Technique and a Comparison of Dosimetry With Conventional Intracavitary Brachytherapy.
We present a new technique of 3-dimensional computed tomography-guided interstitial (IS) brachytherapy (BT) for locally advanced cervical cancer, offering a more advantageous clinical treatment approach. Interstitial BT was performed using an applicator combining uterine tandem and metal needles; needles were inserted freehand under real-time 3-dimensional computed tomography guidance. Twenty-eight patients with bulky tumors and/or parametrial extension (tumor size > 5 cm) after external beam radiotherapy received IS BT. Dosimetric outcomes of the IS BT including the total dose (external beam radiotherapy and high dose-rate BT) D90 for the high-risk clinical target volume (HR-CTV) and D2cc for the organs at risk (OARs) were investigated and compared with a former patient group consisting of 30 individuals who received the conventional intracavitary (IC) BT. The mean D90 values for HR-CTV in the IC BT and IS BT groups were 76.9 ± 5.7 and 88.1 ± 3.3 Gy, respectively. Moreover, 85.7% of the patients received D90 for HR-CTV of 87 Gy or greater in the IS BT group, and only 6.7% of the patients received D90 for HR-CTV of 87 Gy or greater in the IC BT group. The D2cc for the bladder, rectum, and sigmoid were 84.7 ± 6.8, 69.2 ± 4.2, and 67.8 ± 4.5 Gy in the IC BT group and 81.8 ± 6.5, 66.8 ± 4.0, and 64.8 ± 4.1 Gy in the IS BT group. The mean number of needles was 6.9 ± 1.4, with a mean depth of 2.9 ± 0.9 mm for each IS BT. Interstitial BT was associated with only minor complications. The IS BT technique resulted in better dose-volume histogram parameters for large volume tumors (>5 cm) compared with the conventional IC BT and acceptable risk of acute complications in locally advanced cervical cancer and is clinically feasible.


Antiparasitic drugs in neurocysticercosis: albendazole or praziquantel?
This article evaluates the findings and conclusions of a recent meta-analysis of published data comparing the efficacy of the treatment of neurocysticercosis with albendazole and praziquantel in terms of both resolution of brain cysts and seizure control. From 103 related articles indexed in PubMed and the Cochrane Database of Controlled Trials, and quoted in reference lists, six prospective trials comparing albendazole with praziquantel (including patients infected with parasites in their cystic stage without perilesional inflammation and examining partial or total disappearance of cysts and/or control of seizures) were evaluated. The small number and heterogeneity of the included studies makes it difficult to assess the analyses provided. One of the studies was a pilot trial, at least three had grossly inadequate sample sizes and, owing to the way in which the data are presented in one of the studies, it is not possible to extract the proportion of parasites that resolved. None of the studies was designed to evaluate seizure control. The current published data does not provide enough basis to determine conclusively the superiority of either albendazole or praziquantel as first-line treatment of neurocysticercosis, and the choice of an antiparasitic drug is still guided by collateral factors, including drug availability and costs.


Changes in polyphenol profiles and color composition of freshly fermented model wine due to pulsed electric field, enzymes and thermovinification pretreatments.
This work compares the effects of three pretreatments techniques: pulsed electric fields (PEFs), enzymes treatment (ET) and thermovinification (TV) on the improving of extraction of main phenolic compounds, color characteristics (L(∗)a(∗)b(∗)), and composition (copigmentation, non-discolored pigments) of freshly fermented model wine from Cabernet Sauvignon variety. The pretreatments produced differences in the wines, with the color of the freshly fermented model wine obtained from PEF and TV pretreated musts being the most different with an increase of 56% and 62%, respectively, compared to the control, while the color only increased by 22% for ET. At the end of the alcoholic fermentation, the contents of anthocyanins for all the pretreatments were not statistically different. However, for the content of total phenolics and total flavonols, PEF and TV were statistically different, but ET was not statistically different. The contents of flavonols in musts pretreated by PEF and TV were significantly higher comparing to the control. An increase of 48% and 97% was noted respectively, and only 4% for ET. A similar result was observed for the total phenolics with an increase by 18% and 32% respectively for PEF and TV, and only 3% for ET comparing to the control. The results suggest that the higher intensity and the difference of color composition between the control and pretreated freshly fermented model wines were not related only to a higher content of residual native polyphenols in these freshly fermented model wines. Other phenomena such as copigmentation and formation of derived pigments may be favored by these pretreatments.


Successful pregnancy outcome in a Korean patient with symptomatic Wilson's disease.
Wilson's disease is an inherited disease of copper metabolism leading to the toxic accumulation of copper, primarily in the liver and brain. Although the literature shows successful outcomes after proper treatment, pregnant patients with Wilson's disease still need close monitoring and management. Here, we report the case of a successful pregnancy in a Korean woman with Wilson's disease. A 33-year-old primigravid patient with Wilson's disease visited our antenatal clinic. Of her own volition, she had stopped her medication 2 years earlier. Oral zinc oxide therapy was started, and she was closely monitored throughout her pregnancy. She delivered a healthy female infant weighing 3.13 kg through a cesarean section. After delivery, the clinical course of both the mother and the baby were uneventful. We review crucial points in the treatment and the management dilemmas raised by the patient.


Involvement of pro-inflammatory cytokines, mediators of inflammation, and basic fibroblast growth factor in prostaglandin F2alpha-induced luteolysis in bovine corpus luteum.
The process of luteolysis requires very subtly modulated coordination of different factors and regulation systems. Immune cells and cytokines were shown to be relevant for bovine luteolysis. The aim of this study was to investigate the detailed pattern of mRNA expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFalpha), TNF receptor type 1 (TNF-R1), interleukin 1beta (IL-1beta), and interferon gamma (IFNgamma), and of the inducible nitric oxide synthase (iNOS) and the basic fibroblast growth factor (FGF-2) during prostaglandin (PG) F(2alpha)-induced luteolysis in the bovine corpus luteum (CL). In addition, the mRNA expression for the LH-receptor (LH-R) and the steroidogenic enzyme p450scc was determined. Cows in the midluteal phase (Days 8-12) were injected with the PGF(2alpha) analogue cloprostenol, and CL were collected by transvaginal ovariectomy before and 2, 4, 12, 48, and 64 h after PGF(2alpha) injection. Conventional and real-time reverse transcription polymerase chain reaction RT-PCR (LightCycler) using SYBR Green I detection were employed to determine the mRNA expression for the investigated factors. All cytokines were significantly up-regulated during induced luteolysis. LH-R and p450scc mRNA were down-regulated (P < 0.05) during structural luteolysis (after 12 h), and p450scc in addition at 2 h after PGF(2alpha) (P < 0.05). FGF-2 expression increased (P < 0.001) during functional luteolysis (until 12 h after PGF(2alpha)) and diminished thereafter. The mRNA expression for iNOS decreased (P < 0.05) after induction of luteolysis. In conclusion, cytokines may be involved not only in structural but also in functional luteolysis and the deprivation of luteal survival factors, leading to a situation where apoptosis can occur. FGF-2 may participate in the suppression of cytokine-induced iNOS mRNA expression and in the prevention of an inflammatory reaction in the surrounding tissues.


Influence of Lattice Polarizability on the Ionic Conductivity in the Lithium Superionic Argyrodites Li6PS5X (X = Cl, Br, I).
In the search for novel solid electrolytes for solid-state batteries, thiophosphate ionic conductors have been in recent focus owing to their high ionic conductivities, which are believed to stem from a softer, more polarizable anion framework. Inspired by the oft-cited connection between a soft anion lattice and ionic transport, this work aims to provide evidence on how changing the polarizability of the anion sublattice in one structure affects ionic transport. Here, we systematically alter the anion framework polarizability of the superionic argyrodites Li6PS5X by controlling the fractional occupancy of the halide anions (X = Cl, Br, I). Ultrasonic speed of sound measurements are used to quantify the variation in the lattice stiffness and Debye frequencies. In combination with electrochemical impedance spectroscopy and neutron diffraction, these results show that the lattice softness has a striking influence on the ionic transport: the softer bonds lower the activation barrier and simultaneously decrease the prefactor of the moving ion. Due to the contradicting influence of these parameters on ionic conductivity, we find that it is necessary to tailor the lattice stiffness of materials in order to obtain an optimum ionic conductivity.


[Physiology of the pi in Su Wen and Ling Shu in comparison with the spleen in Dutch medicine].
The physiological function of the pi (translated in English as spleen) in traditional Chinese medicine is generally known as the promotion of digestion. But the concept of pi has changed with the times. According to the Su Wen and the Ling Shy, the pi does not directly take part in digestion. These writings often describe the pi as the "pi merdian", considered to contribute to the function of the circulatory system. Comparing the descriptions of the pi in Su Wen and Ling Shu with those of the spleen in Dutch medical books published in the Edo period, we found the following similarities between these two different kinds of medical concepts. Both the pi in the former and the spleen in the latter are considered to be important in transportation of lymph. Furthermore, the pi meridian and jinye (body fluid) in the former correspond to the lymphatic vessel and lymph in the latter, respectively. ...


Nature, severity and correlates of psychological distress in women admitted to a private mother-baby unit.
To characterize psychological distress of women admitted with their infants to a private hospital mother-baby unit. A cross-sectional self-report survey including standardized psychometric questionnaires of consecutive admissions to Masada Private Hospital Mother-Baby Unit, Melbourne between 1 June and 30 November 1997. Scores on the Profile of Mood States, Edinburgh Postnatal Depression Scale, Intimate Bonds Measure, Parental Bonding Instrument, Social Support Questionnaire, Vulnerable Personality Scale self-report instruments and responses to a structured self-report questionnaire. Of the women admitted, 109 out of 146 participated in the survey. Clinically significant fatigue was almost universal in this cohort. Psychological distress clustered into three distinct groups: (i) probable depression; (ii) fatigue and distress; and (iii) fatigue only. It may be more accurate to conceptualise postpartum psychological distress either as a continuum, or as a wide range of distinct states, rather than as a dichotomous condition in which individuals are categorized as being or not being cases. In this cohort, the severity of distress was associated most consistently with the quality of a woman's relationship with her partner and with infants who were difficult to settle. It appears that some cases of psychological distress in women following childbirth may be inaccurately conceptualised as depression. Clinically significant fatigue and moderate distress are distinguishable from depression, and warrant specifically tailored assessment strategies and treatments. Following the birth of a baby, the partner of a mother has a strong influence on her emotional health and should be included in any assessment and intervention.


RNA interference-mediated depletion of N-ethylmaleimide sensitive fusion protein and synaptosomal associated protein of 25 kDa results in the inhibition of blood feeding of the Gulf Coast tick, Amblyomma maculatum.
The signalling pathways in tick salivary glands that control 'sialo-secretome' secretion at the tick-host interface remain elusive; however, this complex process is essential for successful feeding and manipulation of the host haemostatic response. Exocytosis of the sialo-secretome in the salivary glands requires a core of soluble N-ethylmaleimide-sensitive fusion (NSF) attachment proteins (SNAPs) and receptor proteins (SNAREs). SNAREs have been identified as the key components in regulating the sialo-secretome in the salivary gland cells. In this study, we utilized RNA interference to investigate the functional role of two Amblyomma maculatum SNARE complex proteins, AmNSF and AmSNAP-25, in the tick salivary glands during extended blood feeding on the vertebrate host. Knock-down of AmNSF and AmSNAP-25 resulted in death, impaired feeding on the host, lack of engorgement and inhibited oviposition in ticks. Depletion also led to important morphological changes in the collapse of the Golgi apparatus in the salivary gland cells. Our results imply a functional significance of AmNSF and AMSNAP-25 in prolonged tick feeding, and survival on the host. Further characterization of the factors that regulate exocytosis may lead to novel approaches to prevent tick-borne diseases.


Evolution of the Ureteral Stent: The Pivotal Role of the Gibbons Ureteral Catheter.
To review the pioneering contributions of Dr. Robert Gibbons of Virginia Mason Medical Center to the evolution and development of the modern ureteral stent. We reviewed Dr. Gibbons' extensive work through primary sources, including interviews, projector slides, radiology images, stent prototypes, his personal writings, and archived documents. In addition, we performed a review of historical texts and manuscripts describing important innovations in the development of the ureteral stent. In 1972, motivated by a desire to provide his patients with a long-term alternative to open nephrostomy and inspired by Drs. David Davis and Paul Zimskind, who in 1967 had described the use of indwelling ureteral silicone tubing, Dr. Gibbons began to experiment with modifications to improve upon existing stents. To address distal migration, Dr. Gibbons added "wings" that collapsed as the stent was advanced and expanded once in proper position to secure the stent in place. Barium was embedded into the proximal tip to facilitate radiographic visualization. A flange was added to the distal end, preventing proximal migration and minimizing trigonal irritation, and a tail was attached to aid in stent removal. The result was the original Gibbons stent, the first commercially available ureteral stent, and the establishment of Current Procedural Terminology code 52332, still used today. The ureteral stent is a fundamental component of urologic practice. In developing the Gibbons stent, Dr. Gibbons played a pivotal role in addressing the challenge of internal urinary diversion particularly for those who needed long-term management. Urologists and the patients they serve owe Dr. Gibbons and other surgeon-inventors a debt of gratitude for their innovative work.


An unusual electrocardiographic pattern of left ventricular endocardial pacing.
Pacemaker stimulation of the left ventricle is expected to yield a pattern of complete right bundle branch block, however, unusual patterns have been reported. The present report is a case of an unusual electrocardiographic pattern from left ventricular endocardial pacing in a patient with an atrial septal defect and acute myocarditis complicated by complete degree atrioventricular block.


A cross-sectional study of DMFT and CPITN scores in a group of Indonesian soldiers.
A cross-sectional clinical study showed that the prevalence of caries among Indonesian soldiers was low, compared with that found in corresponding Western populations. Also, the progression of caries was very slow, and caries was limited almost exclusively to the occlusal surfaces of the teeth. Among officers, the prevalence of caries was lower than it was among other ranks of the same age. The low general prevalence of caries among Indonesian soldiers may be related to diet. Rice was the major source of carbohydrate for the soldiers, and their sucrose consumption was 10 kg per person per year. Their drinking water contained a low concentration of fluoride (0.1 ppm). In spite of massive accumulations of calculus, the periodontal health of young soldiers (less than 26 yr) was also good. Among those in higher age groups, however, periodontal health had deteriorated, but even in a group aged 40-46 yr, no teeth had been lost as a result of periodontal disease. Among officers, periodontal health was better than it was amongst other ranks of corresponding age. The officers had been accustomed to brushing their teeth regularly, whereas the other ranks had not. It thus appears that toothbrushing may help to preserve periodontal health, even when large amounts of calculus are present on the teeth and there is no opportunity for it to be removed regularly by a dentist.


Heat susceptibility of bacterial enteropathogens. Implications for the prevention of travelers' diarrhea.
The heat susceptibility of four bacterial enteropathogens in foods and water was studied to develop effective recommendations for travelers to regions where diarrheal diseases are important health problems. All enteropathogens tested survived well in foods stored at refrigerator temperature (4 degrees C), room temperature (25 degrees C), and 50 degrees C, which is too hot to touch. Tap water had to be heated above 65 degrees C to reliably kill all bacterial enteropathogens. At 13 of the 14 tourist-oriented hotels in four countries, water from the hot water tap did not reach temperatures of 65 degrees C. The implications of this study are that food and water that are too hot to touch may still be contaminated with bacterial enteropathogens. Travelers should be advised that food, water, or beverages are safe only if they have been brought to boiling or near-boiling temperatures prior to consumption.


Effect of hyperglycemia and hyperinsulinemia on glutathione peroxidase activity in non-obese women with polycystic ovary syndrome.
In order to gain deeper insight into molecular mechanisms underlying oxidative stress (OS) and its relation to insulin resistance and hyperandrogenemia, plasma markers of OS and antioxidant glutathione-peroxidase (GPX) activity were studied in non-obese polycystic ovary syndrome (PCOS) women via the oral glucose tolerance test (OGTT) and hyperinsulinemic euglycemic clamp. In 36 PCOS women, plasma nitrotyrosine, thiol groups, uric acid (UA) and GPX activity were studied during OGTT and clamp. Insulin resistance was assessed by the homeostasis model (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Matsuda insulin sensitivity index (ISI) and M/I ratio. In PCOS patients, significant positive correlations were obtained for UA with testosterone (r=0.385, p=0.039) as well as indices of insulin resistance. Acute hyperglycemia during OGTT induced alteration in both OS markers and GPX. The change in nitrotyrosine and GPX during OGTT correlated with testosterone (r=0.543, p=0.036 and r=-0.457, p=0.025, respectively). The most significant association was found between OS markers and ISI. Our results indicate that non-obese PCOS women are prone to oxidative stress induced by hyperglycemia, but this seems not to be related to the direct effect of hyperinsulinemia during clamp. Oxidative stress markers correlated with indices of insulin resistance and circulating testosterone.


Fine structural changes of Acetobacter suboxydans during growth in a defined medium.
Cytological differences were observed between stationary- and exponentialphase cells of Acetobacter suboxydans grown in a defined medium. Unstained cells observed with the light microscope just after entering the stationary phase differed from exponentially growing cells in that the former exhibited localized increases in density, particularly in the polar regions. Electron microscopy of thin sections revealed that early stationary-phase cells possessed predominantly polar complexes of intracytoplasmic membranes accompanied by polar increases in ribosomal material. When cultures were allowed to continue far into the stationary phase, cells contained extensive aggregations of membrane-like material as the predominant fine-structural feature. In contrast, thin sections of exponentially growing cells exhibited only occasional indications of intracytoplasmic membranes. Intracytoplasmic membranes heretofore have been observed only rarely in the heterotrophic Pseudomonadales.


Monte Carlo studies of three-dimensional O1 and O4 phi4 theory related to Bose-Einstein condensation phase transition temperatures.
The phase transition temperature for the Bose-Einstein condensation (BEC) of weakly interacting Bose gases in three dimensions is known to be related to certain nonuniversal properties of the phase transition of three-dimensional O(2) symmetric phi(4) theory. These properties have been measured previously in Monte Carlo lattice simulations. They have also been approximated analytically, with moderate success, by large N approximations to O(N) symmetric phi(4) theory. To begin investigating the region of validity of the large N approximation in this application, the same Monte Carlo technique developed for the O(2) model [P. Arnold and G. Moore, Phys. Rev. E 64, 066113 (2001)] to O(1) and O(4) theories has been applied. The results indicate that there might exist some theoretically unanticipated systematic errors in the extrapolation of the continuum value from lattice Monte Carlo results. The final results show that the difference between simulations and next-to-leading order large N calculations does not improve significantly from N=2 to N=4. This suggests that one would need to simulate yet larger N's to see true large N scaling of the difference. Quite unexpectedly (and presumably accidentally), the Monte Carlo result for N=1 seems to give the best agreement with the large N approximation among the three cases.


A multiparameter test of clot formation and fibrinolysis for in-vitro drug screening.
A large spectrum of methods has been used in both routine and scientific studies of the hemostatic system. The particular interest of the investigators has been focused on methods simultaneously evaluating clotting and fibrinolysis processes. The aim of the present study was to develop an optical method for overall evaluation of clot formation and lysis (CL-test) that could be used in drug screening. The CL-test was performed in citrate plasma diluted with Tris-buffered saline. Thrombin was applied for plasma clotting (0.5 IU/ml), while tissue plasminogen activator (60 ng/ml) was used for fibrinolysis activation. Clot formation and lysis were monitored in thermostatic conditions (37 degrees C) as a continuous record of transmittance change. By means of own computer program, kinetic parameters of the processes studied and plasma overall clot formation and fibrinolysis potential, expressed as the area under the clotgeneration and fibrinolysis curves, were calculated. The CL-test was developed and checked by evaluation of the effect, on clot formation and lysis, of various concentrations of acetylsalicylic acid (a drug that affects hemostasis), aprotinin (fibrinolysis activator) and venoruton (fibrinolysis inhibitor). The obtained results confirmed that the test we propose for monitoring clot formation, stabilization and lysis is sensitive and enables precise estimation of the processes studied. In our opinion, it can be a useful tool in drug screening investigations.


Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases.
We have previously described a novel series of low molecular weight protein tyrosine kinase inhibitors which we named tyrphostins. The characteristic active pharmacophore of these compounds was the hydroxy-cis-benzylidenemalononitrile moiety. In this article we describe three novel groups of tyrphostins: (i) one group has the phenolic moiety of the cis-benzylidenemalononitrile replaced either with other substituted benzenes or with heteroaromatic rings, (ii) another is a series of conformationally constrained derivatives of hydroxy-cis-benzylidenemalononitriles in which the malononitrile moiety is fixed relative to the aromatic ring, and (iii) two groups of compounds in which the position trans to the benzenemalononitrile has been substituted by ketones and amides. Among the novel tyrphostins examined we found inhibitors which discriminate between the highly homologous EGF receptor kinase (HER1) and ErbB2/neu kinase (HER2). These findings may lead to selective tyrosine kinase blockers for the treatment of diseases in which ErbB2/neu is involved.


Dual and Opposing Regulation of MMP1 and MMP13 by Both Arms of miR-675 in Human Articular Chondrocytes.
MicroRNAs (miRs) are transcribed as stem-loop precursors harboring two different miRs on either side of the structure. Both miRs can modulate levels of cellular transcripts based on sequence complementarity between the miR and the mRNA target. The miR of the current study, miR-675, is encoded in the H19 gene with high expression in fetal/placental tissues but low levels in most adult tissues except for skeletal muscle and articular cartilage. miR-675 has a supportive role in expression of the major collagen component of articular cartilage (COL2A1) but it is unknown which arm contributes to this effect. Objectives: To determine the active arm of miR-675 in human articular chondrocytes. To evaluate effects of overexpression of both arms of miR-675 on MMP1 and MMP13, two enzymes involved in breakdown of COL2A1. To investigate whether abundance of both arms of miR-675 is dynamic. miR-arm activity was determined by association with the AGO2 complex using immunoprecipitation with an AGO2 specific antibody. miR overexpression and inhibition was used to identify indirect downstream effects on two targets of the Matrix-Metalloprotease family, MMP1 and MMP13. Data was evaluated by qPCR and enzymatic activity assays. Early passage human articular chondrocytes (up to passage 2) obtained from cartilage from both healthy and osteoarthritis affected tissue were used. To evaluate miR-675 levels in a different model, myotube differentiation was employed. We show that both arms of miR-675 have opposing effects on MMP1 and MMP13; however only one arm, miR-675-3' is active in human articular chondrocytes. We demonstrate that during myotube differentiation, high expression of both arms of miR-675 is observed as well as an increase in expression of MMP1. We show that both arms of miR-675 result in opposing effects on two downstream molecules MMP1 and MMP13. We propose that miR abundance may arise as response to direct target transcript levels and are thus dynamic to meet the requirements of the cellular environment.


Brain region-specific effects of long-term caloric restriction on redox balance of the aging rat.
Caloric restriction (CR) is the most effective intervention to improve health span and extend lifespan in preclinical models. This anti-aging effect of CR is related to attenuation of oxidative damage in various tissues, with divergent results in the brain. We addressed how brain oxidoreductive balance would be modulated in male Sprague-Dawley (SD) rats submitted to a 40% CR from 8 to 19 months of age, by reference to ad libitum-fed (AL) rats at 2 and 19 months of age. Four brain structures were compared: hippocampus, striatum, parietal cortex, cerebellum. Our CR diet elicits significant prevention of oxidative damages with the upregulation of antioxidant defenses (levels of glutathione [GSH], mRNAs of clusterin and of three key antioxidant enzymes) as compared to age-matched AL controls, in a strikingly region-specific pattern. CR also prevented a drastic rise of the glial fibrillary acidic protein in the hippocampus of old AL rats. Besides, the CR effects at age 19 months mainly consist in improving endogenous defenses before the onset of age-related redox alterations. These effects are more prominent in the hippocampus.


Phase behavior of dipolar fluids from a modified statistical associating fluid theory for potentials of variable range.
A statistical associating fluid theory for potentials of variable range to model dipolar fluids is presented. The new theory, termed the SAFT-VR+D equation (the statistical associating fluid theory for potentials of variable range plus dipole), explicitly accounts for dipolar interactions and their effect on the structure of the fluid. This is achieved through the use of the generalized mean spherical approximation (GMSA) to describe a reference fluid of dipolar square-well segments. Isothermal-isobaric and Gibbs ensemble Monte Carlo simulations have been performed in order to test the new theoretical approach. Predictions for the thermodynamic properties and phase behavior of dipolar square-well monomer and chain fluids, in which one or more segments are dipolar, are considered and compared with new computer simulation data. The results show that the equation of state in general provides a good description of the phase behavior of dipolar monomer and chain fluids. Some deviations are seen between the simulation data and theoretical predictions for monomer fluids with large dipole moments and for molecules composed of segments with dipoles in different orientations. This is addressed through the replacement of the GMSA by the linearized exponential approximation.


The impact of the COVID-19 pandemic on health-care delivery system for other diseases and antimicrobial resistance threat in India.
India's health-care delivery is challenged with different inequalities and theelivery is challenged with different inequalities and the dual burden of communicable and noncommunicable diseases. Lockdown posed negative effects on the growth and economy of the country; simultaneously, some positive effects, like increased health consciousness and adoption of hygienic practices, were also there. Health-care delivery system faced tremendous challenges in diagnostics, therapeutics, infrastructure for inpatient care, and protection of health-care manpower. During this period, people chose to self medicate which in turn increased the threat of emergence of antimicrobial resistance. Due to shifting priority to COVID from other diseases, resources were shifted to COVID, affecting the management of other acute and chronic diseases. The launching of COVID-19 vaccination campaign showed some hope. However, despite the vaccination drive, strengthening infrastructure, and surveillance system, the devastating second wave could not be avoided due to the conglomeration of the crowd for pilgrimage, election campaign, and tourism in an unrestricted manner. It may be concluded that the fourth wave may be short lasting due to increased herd immunity.


Quantification of Serum Sulfamethoxazole and Trimethoprim by Ultra-fast Solid-Phase Extraction-Tandem Mass Spectrometry.
The combination of trimethoprim (TMP) and sulfamethoxazole (SMX) is used to treat a number of bacterial infections. TMP/SMX concentrations in serum are conventionally monitored using high-performance liquid chromatography (HPLC) or liquid chromatography tandem mass spectrometry. These methods require laborious manual extraction techniques and relatively long sample analysis times, necessitating the development of a simple, high-throughput method. A simple, high-throughput method to measure TMP/SMX using ultra-fast solid-phase extraction (SPE)-tandem mass spectrometry has been developed. Calibration standards, quality control materials, and patient samples were precipitated with acetonitrile containing isotopically labeled internal standards. Samples were vortexed, centrifuged for 5 minutes at 2053g, and the resulting supernatant was diluted in aqueous mobile phase and injected onto the C18 SPE cartridge. MS/MS analysis was performed by electrospray ionization in positive ion mode at a rate of <20 seconds per sample. A 5-point linear 1/x calibration curve was used to calculate sample concentrations. The intra-assay precision coefficients of variation were <6% and <7% for SMX and TMP, respectively, and <10% for both interassay precision coefficients of variation. Comparison studies using 50 patient and spiked serum samples showed r values of 0.9890 and 0.9853 and y-intercept values of -1.918 and -1.357, respectively compared with the HPLC reference method. All data points were <±15% of the mean. Linearity [r = 0.9952 (SMX) and 0.9954 (TMP)] was established from 12 to 400 mcg/mL with a detection limit of 0.47 mcg/mL, and 1.2-40 mcg/mL with a detection limit of 0.06 mcg/mL, for SMX and TMP, respectively. For either drug, no significant carryover was observed after samples at the upper limit of quantification. No interference was observed from any of the 77 drugs and respective metabolites tested. A high-throughput SPE-tandem mass spectrometry method for TMP/SMX quantification was developed. The <20 seconds analysis time is a significant improvement compared with traditional HPLC and liquid chromatography tandem mass spectrometry methods, without sacrificing analytical performance.


Primary Jejunal Gastrointestinal Stromal Tumor: Diagnosis Delay of 3 Years but Successful Management in Early Stage (II) by Surgery and Adjuvant Therapy.
In the digestive system, mesenchymal origin of tumors is quite rare; in general, they are recognized as gastrointestinal stromal tumors (GISTs). The incidence of GISTs is very low (2 in 100,000), while jejunal GISTs are extremely rare, accounting for 0.1-3% of all gastrointestinal (GI) tumors. Small intestinal GISTs are the second most common (25%) site in the GI tract, usually occurring in the duodenum. We present the case of a 62-year-old Bangladeshi female with a history of GI bleeding 3 years earlier; the cause of the bleeding had not been found despite extensive investigations. In the meantime, the patient had developed occasional abdominal pain and lumpy feelings in the right side of the abdomen without any GI bleeding. Exploratory laparotomy was carried out in view of a small intestinal mesenteric mass in a computed tomography scan. On midline incision there was a 6 × 6 cm mass in the antimesenteric border of the jejunum approximately 30 cm from the duodenojejunal flexure, which was resected followed by anastomosis. The presentation of GISTs ranges from asymptomatic to mild abdominal pain and mass (5-50%) and mechanical obstruction (5%) as well as hemorrhage - perforation having rarely been reported (0.8%) - making the diagnosis difficult. Exophytic growth of these tumors has been noted in 18-30% of cases. In view of intermediate risk of malignancy, the patient was started with adjuvant imatinib 400 mg once daily due to probability of disease recurrence (24%).


Relationship Between Endogenous Hydrogen Sulfide and Pulmonary Vascular Indexes on High-Resolution Computed Tomography in Patients with Chronic Obstructive Pulmonary Disease.
To explore the relationship between endogenous hydrogen sulfide (H2S) and high-resolution computed tomography (HRCT) indexes in pulmonary vascular remodeling. A total of 94 stable chronic obstructive pulmonary disease (COPD) patients were recruited for the study.Plasma H2S levels were measured using fluorescence probe. Fluorescence quantitative polymerase chain reaction was used to measure H2S synthase cystathionine-γ-lyase (CSE) mRNA and cystathionine-β-synthesis enzyme (CBS) mRNA. The main pulmonary artery diameter (mPAD), axial diagonal mPAD, coronal mPAD, sagittal mPAD, right pulmonary artery diameter (RPAD), left pulmonary artery diameter (LPAD), and ascending aortic diameter (AAD) and the percentage of total cross-sectional area of vessels less than 5 mm2 of total lung area (%CSA <5) on HRCT were measured. Pulmonary arterial systolic pressure (PASP) of echocardiography, blood gas analysis, and routine blood tests were performed. Correlation analysis and multivariate linear regression were performed using SPSS 22.0. H2S was negatively correlated with mPAD, axial diagonal mPAD, and sagittal mPAD (r = -0.25~-0.32) and positively correlated with PaO2 (r = 0.35). Relative expression of CSE mRNA was positively correlated with PASP, coronal mPAD, sagittal mPAD, white blood cell count (WBC), and neutrophil count (N) (r = 0.30~0.44). The relative expression of CBS mRNA was positively correlated with PASP, WBC, and N (r = 0.34~0.41). In separate models predicting pulmonary vascular indexes, a 1μmol/L increase in H2S predicted lower pulmonary artery diameter (for axial diagonal mPAD, 0.76mm lower; for mPAD/AAD, 0.68mm lower). All P values were less than 0.05. Endogenous H2S may be involved in pulmonary vascular remodeling, providing a new method for the diagnosis and treatment of COPD. The generation of H2S may be inhibited by hypoxia, inflammation, etc.


Effects of gene polymorphisms of metabolic enzymes on the association between red and processed meat consumption and the development of colon cancer; a literature review.
The role of environmental factors and genetic susceptibility in the development of colon cancer (CC) has been already proven, but the role of gene polymorphisms in modifying the risk of environmental factors such as nutritional factors is still unknown. This study aimed to investigate the effect of polymorphisms of involved genes in the association between red meat consumption and the development of CC. The present review was carried out using keywords such as polymorphism and/or protein and/or red meat and/or processed meat and/or colon cancer. PubMed and Science Direct databases were used to collect all related articles published from 2001 to 2017. The presence of SNP in the coding genes of proteins involved in metabolism of nutrients could play significant roles in the extent of the effects of nutrition in the development of CC. The effect of dietary proteins greatly depends on the polymorphisms in the metabolising genes of these substances. Gene polymorphisms may have a role in colorectal cancer risk, especially in people with high meat intake, and this leads to a difference in the effects of meat consumption in different individuals. To conclude, dietary recommendations for the prevention and control of CC should be modified based on the genotype of different individuals. Increasing our knowledge on this field of nutritional genomics can lead to personalised preventive and therapeutic recommendations for CC patients.


A weighted bootstrap approach to logistic regression modelling in identifying risk behaviours associated with sexual activity.
The latest population estimates released by Statistics South Africa indicate that 25.03% of all deaths in 2017 in South Africa were AIDS-related. Along with these results, it is also reported that 7.06% of the population were living with HIV, with the HIV-prevalence among youth (aged 15-24) at 4.64% for 2017 (STATSSA. (2018). Retrieved from Statistics South Africa: http://www.statssa.gov.za/publications/P0302/P03022017.pdf ). The data used in the study contained information related to the risk-taking behaviours associated with the sexual activity of entering first-year students at the University of the Western Cape. In this study, a logistic regression modelling procedure was carried out on those students that were determined to be sexually active, therefore, in the modelling procedure significant risk behaviours of sexually active first-year students could be identified. Of the 14 variables included in the modelling procedure, six were found to be significantly associated with sexually active students. The significant variables included; the age and race of the student, whether the student had ever taken an HIV test, the importance of religion in influencing the sexual behaviour of the student, whether the student consumed alcohol and lastly whether the student smoked. This study further investigated the impact of introducing sample weighting, bootstrap sampling as well as variable selection methods into the logistic regression modelling procedure. It is shown that incorporating these techniques into the modelling procedure produces logistic regression models that are more accurate and have an increased predictive capability. The bootstrapping procedure is shown to produce logistic regression models that are more accurate than those produced without a bootstrap procedure. A comparison between 200, 500 and 1000 bootstrap samples is also incorporated into the modelling procedure with the models produced from 200 bootstrap samples shown to be just as accurate those produced from 500 or 1000 bootstrap samples. Of the five variable selection methods used, it is shown that the Newton-Raphson and Fisher methods are unreliable in producing logistic regression models. The forward, backward and stepwise variable selection methods are shown to produce very similar results.


Identification and characterization of CYP79D6v4, a cytochrome P450 enzyme producing aldoximes in black poplar (Populus nigra).
After herbivore feeding, poplar trees produce complex volatile blends containing terpenes, green leaf volatiles, aromatics, and nitrogen-containing compounds such as aldoximes and nitriles. It has been shown recently that volatile aldoximes released from gypsy moth (Lymantria dispar) caterpillar-damaged black poplar (Populus nigra) trees attract parasitoids that are caterpillar enemies. In western balsam poplar (P. trichocarpa), volatile aldoximes are produced by 2 P450 monooxygenases, CYP79D6v3 and CYP79D7v2. A gene fragment with high similarity to CYP79D6/7 was recently shown to be upregulated in herbivore-damaged leaves of P. nigra. In the present study we report the cloning and characterization of this gene, designated as CYP79D6v4. Recombinant CYP79D6v4 was able to convert different amino acids into the corresponding aldoximes, which were also found in the volatile blend of P. nigra. Thus, CYP79D6v4 is most likely involved in herbivore-induced aldoxime formation in black poplar.


Total Syntheses of Cystobactamids and Structural Confirmation of Cystobactamid 919-2.
The cystobactamids are a family of antibacterial natural products with unprecedented chemical scaffolds that are active against both Gram-positive and Gram-negative pathogens. Herein, we describe the first total synthesis of cystobactamid 919-2 from three fragments. Our convergent synthesis enabled both the confirmation of the correct structure and the determination of the absolute configuration of cystobactamid 919-2.


Synchronization in networks of spatially extended systems.
Synchronization processes in networks of spatially extended dynamical systems are analytically and numerically studied. We focus on the relevant case of networks whose elements (or nodes) are spatially extended dynamical systems, with the nodes being connected with each other by scalar signals. The stability of the synchronous spatio-temporal state for a generic network is analytically assessed by means of an extension of the master stability function approach. We find an excellent agreement between the theoretical predictions and the data obtained by means of numerical calculations. The efficiency and reliability of this method is illustrated numerically with networks of beam-plasma chaotic systems (Pierce diodes). We discuss also how the revealed regularities are expected to take place in other relevant physical and biological circumstances.


Effect of angiotensin II and losartan on the phagocytic activity of peritoneal macrophages from Balb/C mice.
Angiotensin II (AII), a product of rennin-angiotensin system, exerts an important role on the function of immune system cells. In this study, the effect of AII on the phagocytic activity of mouse peritoneal macrophages was assessed. Mice peritoneal macrophages were cultured for 48 h and the influence of different concentrations of AII (10(-14) to 10(-7) M) and/or losartan, 10(-16) to 10(-6) M), an AT1 angiotensin receptor antagonist, on phagocytic activity and superoxide anion production was determined. Dimethylthiazoldiphenyltetrazolium bromide reduction and the nucleic acid content were used to assess the cvtotoxicity of losartan. A stimulatory effect on phagocytic activity (P < 0.05) was observed with 10(-13) M and 10(-12 M) AII concentrations. The addition of losartan (up to10(-14) M) to the cell cultures blocked (P < 0.001) the phagocytosis indicating the involvement of AT1 receptors. In contrast, superoxide anion production was not affected by AII or losartan. The existence of AT1 and AT2 receptors in peritoneal macrophages was demonstrated by immunofluorescence microscopy. These results support the hypothesis that AII receptors can modulate murine macrophage activity and phagocytosis, and suggest that AII may have a therapeutic role as an immunomodulatory agent in modifying the host resistance to infection.


A Genetic Map of Ostrich Z Chromosome and the Role of Inversions in Avian Sex Chromosome Evolution.
Recombination arrest is a necessary step for the evolution of distinct sex chromosomes. Structural changes, such as inversions, may represent the mechanistic basis for recombination suppression and comparisons of the structural organization of chromosomes as given by chromosome-level assemblies offer the possibility to infer inversions across species at some detail. In birds, deduction of the process of sex chromosome evolution has been hampered by the lack of a validated chromosome-level assembly from a representative of one of the two basal clades of modern birds, Paleognathae. We therefore developed a high-density genetic linkage map of the ostrich Z chromosome and used this to correct an existing assembly, including correction of a large chimeric superscaffold and the order and orientation of other superscaffolds. We identified the pseudoautosomal region as a 52 Mb segment (≈60% of the Z chromosome) where recombination occurred in both sexes. By comparing the order and location of genes on the ostrich Z chromosome with that of six bird species from the other major clade of birds (Neognathae), and of reptilian outgroup species, 25 Z-linked inversions were inferred in the avian lineages. We defined Z chromosome organization in an early avian ancestor and identified inversions spanning the candidate sex-determining DMRT1 gene in this ancestor, which could potentially have triggered the onset of avian sex chromosome evolution. We conclude that avian sex chromosome evolution has been characterized by a complex process of probably both Z-linked and W-linked inversions (and/or other processes). This study illustrates the need for validated chromosome-level assemblies for inference of genome evolution.


Isometric knee extension force in Japanese type 2 diabetic patients without apparent diabetic polyneuropathy: Data from the Multicenter Survey of the Isometric Lower Extremity Strength in Type 2 Diabetes study.
To determine standard reference values for isometric knee extension force using a cohort of Japanese type 2 diabetic patients without diabetic polyneuropathy. Patient data were collected from the Multicenter Survey of the Isometric Lower Extremity Strength in Type 2 Diabetes study and compared with previously published data of healthy control subjects. In total, we enrolled 898 patients with type 2 diabetes aged 30-87 years, who did not have diabetic polyneuropathy. The control group included 510 healthy subjects aged 30-88 years. Maximum isometric knee extension force (KEF) values were obtained by using a hand-held dynamometer with belt stabilization. In addition, KEF (kgf) was adjusted for bodyweight (kg) to calculate %KEF. KEF and %KEF decreased with age in both patients with diabetes and healthy control subjects. The mean values of KEF and %KEF in patients with diabetes were reduced by 9.7% and 20.8%, respectively, in males, and by 11.6% and 23.0%, respectively, in females compared to the values in healthy control subjects. KEF and %KEF in patients with type 2 diabetes without diabetic polyneuropathy may reduce by approximately 10% and 20%, respectively, compared to these values in healthy control subjects. This study provides reference values for isometric KEF with respect to sex in a population covering a wide age range.


A study of a new tumour marker, CYFRA 21-1, in squamous cell carcinoma of the head and neck, and comparison with squamous cell carcinoma antigen.
CYFRA 21-1 (CYFRA) is a newly developed tumour marker which is useful in evaluating large cell lung carcinoma, especially the squamous cell type. The purpose of this study was to assess the clinical value of CYFRA for squamous cell carcinoma of the head and neck and compare the results with squamous cell carcinoma antigen (SCCA). Serum levels of CYFRA were measured in 168 patients with a newly diagnosed head and neck squamous carcinoma. In addition, 77 patients without evidence of neoplasm were included as controls. At the same time, SCCA was also determined. The cut-off values of CYFRA and SCCA, determined at the 95th percentile of the standard Gaussian variate of controls, were 2.48 ng/ml and 1.49 ng/ml respectively. The diagnostic sensitivity of CYFRA was superior to that of SCCA, especially for nasopharyngeal carcinoma. The sensitivity of CYFRA for nasopharyngeal carcinoma was much higher (58.3%) than that of SCCA (15.5%). However, the sensitivity of CYFRA is not satisfactory in all types of squamous carcinoma. For oral cancer, the sensitivity is only 25.6%. CYFRA is a useful serum marker for patients with certain types of head and neck squamous carcinoma, such as nasopharyngeal carcinoma and hypopharyngeal carcinoma. In addition, CYFRA may be also useful in monitoring recurrence of certain types of SCCHN, which are sometimes difficult to detect.


The effect of cue-familiarity, cue-distinctiveness, and retention interval on prospective remembering.
Five experiments investigated the effects of cue familiarity, cue distinctiveness, and retention interval on prospective remembering. Results showed that (1) performance in a prospective memory task is facilitated when the cue is unfamiliar and/or distinctive; and (2) it is impaired by 3-minutes' delay between the instructions and the task (Experiment 1). A beneficial effect of distinctiveness was also found when perceptual rather than semantic distinctiveness was tested (Experiment 2). Experiments 3 and 4 ruled out the hypotheses that "unfulfilled expectancy" of an event (i.e. non-appearance of the cue during training) (Experiment 3), or some sort of "habituation" in the target context (Experiment 4), may have caused the low performance observed in the delayed conditions. Finally, results from Experiment 5 showed that delay negatively affected prospective remembering when it was filled with either a demanding interpolated activity (practice in a STM task) or an undemanding motoric activity (repetitive hands movements). Unfilled delay and an undemanding verbal activity (counting) were found not to affect prospective memory. Implications for the mechanisms underlying prospective remembering are discussed.


Fluctuation in systolic blood pressure is a major systemic risk factor for development of primary open-angle glaucoma.
We evaluated the risk of development of primary open-angle glaucoma (POAG) in terms of variability in BP using a nationwide, population-based, 11-year longitudinal study using the Korean National Health Insurance Research Database. We included patients who underwent health care examinations more than twice between January 2002 and December 2006. We divided all subjects by the quartiles of variability in systolic blood pressure (SBP), diastolic blood pressure (DBP), and the difference between SBP and DBP. Of the total of 80,021 included subjects, 910 were diagnosed with POAG between January 2007 and December 2013. Both the Kaplan-Meier survival curves and log-rank test data indicated that patients with higher-level BP variability developed POAG significantly more frequently than did patients with lower-level variability (P < 0.001). On multivariate Cox's regression modeling including gender, age, sex, household income, smoking status, level of alcohol intake, extent of exercise, diabetes mellitus status, dyslipidemia status, SBP, and DBP; the hazard ratios among the highest and lowest quartiles of SD SBP and CV SBP were 1.256 and 1.238, respectively. Our findings suggest that subjects in the highest quartile of SBP variability were significantly more likely to develop POAG in our population-based sample of Korean adults.


Two Cases of Transcutaneous Electrical Nerve Stimulation of the Common Peroneal Nerve Successfully Treating Refractory, Multifactorial Leg Edema.
The treatment of leg edema often involves promoting venous blood flow but can be difficult in patients with comorbidities that prevent traditional management strategies such as limb elevation or mechanical compression devices. The geko device is a self-contained neuromuscular stimulation device that adheres to skin over the common peroneal nerve and delivers a low-voltage stimulus that activates the lower-leg musculature resulting in enhanced superficial femoral vein blood flow and velocity. Here we report 2 cases of multifactorial and refractory leg edema successfully treated with the geko device over a period of 4 to 16 weeks. The device also improved pain and chronic wound healing. Although the geko device is costly, it was well tolerated and may provide another treatment strategy for resistant leg swelling.


Conformational templation in a singly bridged calix[7]arene derivative induced by alkali metal cations.
The first examples of alkali metal cation conformational templation of a calix[7]arene derivative were found in the alkali salts of 1,4-calix[7]crown-4, which were obtained by its treatment with the corresponding alkali metal carbonates. Competitive experiments showed that potassium and rubidium cations give the most effective templation, with a slight preference for the former. Experimental results and Monte Carlo conformational searches indicated that the cation interacts with all O-atoms including those of the crown-4 bridge.


A Selective Culture Medium for Screening Ceftazidime-Avibactam Resistance in Enterobacterales and Pseudomonas aeruginosa.
The SuperCAZ/AVI medium was developed for screening ceftazidime-avibactam (CZA) resistance among Gram-negative bacteria (Enterobacterales and Pseudomonas aeruginosa). It was evaluated using 50 CZA-susceptible and 42 CZA-resistant Gram-negative isolates. Its sensitivity and specificity of detection were 100%. Excellent performance of the medium was also observed by testing spiked stools, with the lower limit of detection ranging from 101 to 102 CFU/ml. This screening medium provides the opportunity to detect CZA-resistant isolates regardless of their resistance mechanisms.


[Clinico-statistical observation of patients referred from our hospital at the Department of Oral Surgery].
The patients referred from our hospital at the Department of Oral Surgery, University of Tokyo, during the two years from January 1990 to December 1991 were analyzed statistically. The results were as follows: 1. Our subjects were 1,152 patients (24.2% of first-time patients), 540 males and 612 females. 2. Concerning age distribution, the majority was in their forties, fifties and sixties. 3. More patients were from internal medicine, ENT clinic, plastic surgery and cardiothoracic surgery. 4. On the number of patients categorized by disease at other departments, the largest number was cardiovascular disease. 5. On the number of patients categorized by disease at our department, the majority were dental diseases (dental caries, marginal periodontitis and missing teeth).


Telehealth and hospitalizations for Medicare home healthcare patients.
To examine the effect of an integrated, clinician-focused telehealth monitoring system on the probability of hospitalization within the first 30-day episode of home healthcare. Retrospective, nonexperimental design. The study sample includes 2009 data from 5873 Medicare beneficiaries receiving home healthcare services through a network of community-based home health agencies operating in Texas and Louisiana. Propensity-score matching was used to control for selection bias. Logistic regression and postestimation parameter simulation were used to assess how the use of an integrated, clinician-focused telehealth monitoring system might affect the probability of hospitalization during the first 30-day episode of home healthcare. The 30-day probability of hospitalization for telehealth and non-telehealth patients was 10.3% and 17.1%, respectively. Patients in the telehealth group had a 7-percentage-point (95% confidence interval 4.2, 9.4) lower probability of hospitalization within the first 30-day episode of home healthcare than those in the non-telehealth group. The use of an integrated, clinician focused telehealth monitoring system can substantially reduce the 30-day probability of hospitalization for home healthcare patients. Telehealth monitoring systems that integrate skilled clinicians can lead to substantial hospitalization-related cost savings.


Biochemical Parameters in Confirmed Covid-19 Patients: A Hospital Based Study from Eastern Nepal.
Background COVID-19 has posed a global threat to almost every part of the world. The disease has varied form of presentation and the modern medicine has still not been able to provide definite treatment for the disease. Objective To assess the biochemical parameters in confirmed patients of COVID-19 admitted at B.P. Koirala Institute of Health Sciences (BPKIHS), Dharan, Nepal. Method This is a retrospective hospital based cross-sectional study conducted in the Department of Biochemistry, B.P. Koirala Institute of Health Sciences, Dharan from October to December, 2020. Convenient sampling technique was used to enroll the data of the patients for whom the biochemical parameters were requested by the clinicians. Routine biochemical tests were performed in Cobas c311 autoanalyzer. Result A total of 202 patients with confirmed COVID-19 infections and admitted at COVID Hospital, BPKIHS were enrolled. The findings depict an elevated liver enzyme (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase and cardiac enzymes (creatine kinase-total and creatine kinase- MB) in the study population. Increased serum ferritin (1026.08±220.53), hs CRP (41.52±5.22) and lactate dehydrogenase 360 [303.50-526.75] was found in the patients. Also, majority of the patients (> 50%) had abnormal biochemical findings. Conclusion Biomarkers like C-reactive protein, lactate dehydrogenase and ferritin have shown significant clinical implications in effective management, monitoring, and assessment of the severity of disease in COVID- 19 patients. Simple and cost-effective markers like CRP, LDH, HbA1c could be used for monitoring the severity of COVID-19 infection.


Convergence in sympatric swallowtail butterflies reveals ecological interactions as a key driver of worldwide trait diversification.
Ecological interactions can promote phenotypic diversification in sympatric species. While competition can enhance trait divergence, other ecological interactions may promote convergence in sympatric species. Within butterflies, evolutionary convergences in wing color patterns have been reported between distantly related species, especially in females of palatable species, where mimetic color patterns are promoted by predator communities shared with defended species living in sympatry. Wing color patterns are also often involved in species recognition in butterflies, and divergence in this trait has been reported in closely related species living in sympatry as a result of reproductive character displacement. Here, we investigate the effect of sympatry between species on the convergence vs. divergence of their wing color patterns in relation to phylogenetic distance, focusing on the iconic swallowtail butterflies (family Papilionidae). We developed an unsupervised machine learning-based method to estimate phenotypic distances among wing color patterns of 337 species, enabling us to finely quantify morphological diversity at the global scale among species and allowing us to compute pairwise phenotypic distances between sympatric and allopatric species pairs. We found phenotypic convergence in sympatry, stronger among distantly related species, while divergence was weaker and restricted to closely related males. The convergence was stronger among females than males, suggesting that differential selective pressures acting on the two sexes drove sexual dimorphism. Our results highlight the significant effect of ecological interactions driven by predation pressures on trait diversification in Papilionidae and provide evidence for the interaction between phylogenetic proximity and ecological interactions in sympatry, acting on macroevolutionary patterns of phenotypic diversification.


Reaction norms in natural conditions: how does metabolic performance respond to weather variations in a small endotherm facing cold environments?
Reaction norms reflect an organisms' capacity to adjust its phenotype to the environment and allows for identifying trait values associated with physiological limits. However, reaction norms of physiological parameters are mostly unknown for endotherms living in natural conditions. Black-capped chickadees (Poecile atricapillus) increase their metabolic performance during winter acclimatization and are thus good model to measure reaction norms in the wild. We repeatedly measured basal (BMR) and summit (Msum) metabolism in chickadees to characterize, for the first time in a free-living endotherm, reaction norms of these parameters across the natural range of weather variation. BMR varied between individuals and was weakly and negatively related to minimal temperature. Msum varied with minimal temperature following a Z-shape curve, increasing linearly between 24°C and -10°C, and changed with absolute humidity following a U-shape relationship. These results suggest that thermal exchanges with the environment have minimal effects on maintenance costs, which may be individual-dependent, while thermogenic capacity is responding to body heat loss. Our results suggest also that BMR and Msum respond to different and likely independent constraints.


[Hoarding Disorder in DSM-5: Clinical description and cognitive approach].
Hoarding disorder is characterized by difficulty discarding or parting with possessions regardless their actual value as well as, in most cases, persistent acquisition of objects. Possessions are accumulated in large numbers that fill up and clutter active living space to the extent that its intended use is no longer possible resulting to significant functional impairment and/or distress. Saving and difficulty discarding appear to be associated to subjective beliefs about the instrumental, sentimental or intrinsic value of objects. Despite significant impact on the individual, the family and the community, until recently hoarding disorder had been a "neglected" clinical phenomenon. The recent research efforts to study and understand this phenomenon led to significant changes regarding the diagnostic status and therapeutic interventions. It was classified as a distinct diagnostic entity in the recent edition of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association-5th ed. (DSM-5). Hoarding is not considered a symptom of obsessive compulsive disorder or obsessive compulsive personality disorder anymore and it is now ranked among compulsive spectrum disorders. So far the cognitive model for hoarding disorder is the main, widely accepted, clinically and empirically supported theoretical framework for understanding its features. The cognitive model offers an explanation about the predisposing, onset and perpetuating factors of the disorder as well as the basis for the development of specific therapeutic interventions. The cognitive model conceptualizes hoarding disorder as a result of four factors: personal vulnerability (heredity, early experiences and life events, personality traits, interpersonal difficulties), difficulties in information processing (deficits in attention, memory, executive functions such as decision making and categorization), maladaptive cognitive content (meaning of possessions, emotional attachment to possessions, dysfunctional beliefs in relation to the mnemonic ability and memory importance) through which hoarding behaviors are reinforced and finally installed (positive and negative reinforcement, association with positive or negative emotions e.g. pleasure in relation to acquisition/saving and anxiety or discomfort in relation to discarding). The purpose of this article is to inform about this new disorder giving emphasis on recent data in regard to its phenomenology and provide a detailed description of the cognitive model. Finally, a brief mention on the psychotherapeutic and pharmacological interventions is presented. Hoarding Disorder is a difficult clinical problem to treat. Poor insight, ego-syntonic nature of symptoms and treatment resistance are often reported in patients. Further improvement of the therapeutic interventions in order to improve effectiveness and target the high rate of treatment drop out is needed.


Electrochemical (Bio)Sensors Enabled by Fused Deposition Modeling-Based 3D Printing: A Guide to Selecting Designs, Printing Parameters, and Post-Treatment Protocols.
The 3D printing (or additive manufacturing, AM) technology is capable to provide a quick and easy production of objects with freedom of design, reducing waste generation. Among the AM techniques, fused deposition modeling (FDM) has been highlighted due to its affordability, scalability, and possibility of processing an extensive range of materials (thermoplastics, composites, biobased materials, etc.). The possibility of obtaining electrochemical cells, arrays, pieces, and more recently, electrodes, exactly according to the demand, in varied shapes and sizes, and employing the desired materials has made from 3D printing technology an indispensable tool in electroanalysis. In this regard, the obtention of an FDM 3D printer has great advantages for electroanalytical laboratories, and its use is relatively simple. Some care has to be taken to aid the user to take advantage of the great potential of this technology, avoiding problems such as solution leakages, very common in 3D printed cells, providing well-sealed objects, with high quality. In this sense, herein, we present a complete protocol regarding the use of FDM 3D printers for the fabrication of complete electrochemical systems, including (bio)sensors, and how to improve the quality of the obtained systems. A guide from the initial printing stages, regarding the design and structure obtention, to the final application, including the improvement of obtained 3D printed electrodes for different purposes, is provided here. Thus, this protocol can provide great perspectives and alternatives for 3D printing in electroanalysis and aid the user to understand and solve several problems with the use of this technology in this field.


Acrolein, a toxicant in cigarette smoke, causes oxidative damage and mitochondrial dysfunction in RPE cells: protection by (R)-alpha-lipoic acid.
To understand better the cell and molecular basis for the epidemiologic association between cigarette smoke, oxidant injury, and age-associated macular degeneration, the authors examined the effects of acrolein, a major toxicant in cigarette smoke, on oxidative mitochondrial damage in retinal pigment epithelial (RPE) cells and the reduction of this damage by lipoic acid. Cultured human ARPE19 cells and primary cultures of human fetal (hf)RPE were treated with acrolein. The toxicity of acrolein and the protective effects of R-alpha-lipoic acid were examined with a variety of previously described techniques. Acute acrolein exposure exceeding 50 microM (24 hours) in ARPR19 cells caused toxicity, including decreases in cell viability, mitochondrial potential, GSH, antioxidant capacity, Nrf2 expression, enzyme activity (mitochondrial complexes I, II, III; superoxide dismutase; and glutathione peroxidase). Acute exposure also increased oxidant levels, protein carbonyls, and calcium. Continuous acrolein exposure over 8 or 32 days caused similar toxicity but from 10- to 100-fold lower doses (0.1-5 microM). Pretreatment with R-alpha-lipoic acid effectively protected ARPE-19 cells from acrolein toxicity. Primary hfRPE cells were comparable to the ARPE-19 cells in sensitivity to acrolein toxicity and lipoic acid protection. These results show that acrolein is a mitochondrial toxicant in RPE cells and that acrolein-induced oxidative mitochondrial dysfunction is reduced by lipoic acid. The similar sensitivity of the ARPE-19 and hfRPE cells suggests that both models are useful for studying RPE toxicity and protection. These experiments indicate that mitochondria-targeted antioxidants such as lipoic acid may be an effective strategy for reducing or preventing chronic oxidant-induced RPE degeneration in vivo from a variety of sources, including cigarette smoke.