Gafchromic EBT3 film dosimetry in electron beams - energy dependence and improved film read-out.
For megavoltage photon radiation, the fundamental dosimetry characteristics of Gafchromic EBT3 film were determined in 60Co gamma ray beam with addition of experimental and Monte Carlo (MC)-simulated energy dependence of the film for 6 MV photon beam and 6 MeV, 9 MeV, 12 MeV, and 16 MeV electron beams in water phantom. For the film read-out, two phase correction of scanner sensitivity was applied: a matrix correction for scanning area and dose-dependent correction by iterative procedure. With these corrections, the uniformity of response can be improved to be within ± 50 pixel values (PVs). To improve the read-out accuracy, a procedure with flipped film orientations was established. With the method, scanner uniformity can be improved further and dust particles, scratches and/or dirt on scan-ner glass can be detected and eliminated. Responses from red and green channels were averaged for read-out, which decreased the effect of noise present in values from separate channels. Since the signal level with the blue channel is considerably lower than with other channels, the signal variation due to different perturbation effects increases the noise level so that the blue channel is not recommended to be used for dose determination. However, the blue channel can be used for the detection of emulsion thickness variations for film quality evaluations with unexposed films. With electron beams ranging from 6 MeV to 16 MeV and at reference measurement conditions in water, the energy dependence of the EBT3 film is uniform within 0.5%, with uncertainties close to 1.6% (k = 2). Including 6 MV photon beam and the electron beams mentioned, the energy dependence is within 1.1%. No notable differences were found between the experimental and MC-simulated responses, indicating negligible change in intrinsic energy dependence of the EBT3 film for 6 MV photon beam and 6 MeV-16 MeV electron beams. Based on the dosimetric characteristics of the EBT3 film, the read-out procedure established, the nearly uniform energy dependence found and the estimated uncertainties, the EBT3 film was concluded to be a suitable 2D dosimeter for measuring electron or mixed photon/electron dose distributions in water phantom. Uncertainties of 3.7% (k = 2) for absolute and 2.3% (k = 2) for relative dose were estimated.


"Love hurts": romantic attachment and depressive symptoms in pregnant adolescent and young adult couples.
The current study investigates the relationship between romantic attachment style and depressive symptoms between both members of pregnant adolescent and young adult couples. Participants were 296 pregnant young females (mean age = 18.7) and their male partners (mean age = 21.3; 592 total participants) who were recruited from obstetrics and gynecology clinics in Connecticut. The dimensions of avoidant and anxious romantic attachment were assessed using the Experiences in Close Relationships Inventory. Depressive symptoms were measured using the Center for Epidemiological Studies-Depression Scale. Results showed that avoidant attachment and anxious attachment were significantly positively related to depressive symptoms. Multilevel modeling for partner effects revealed that anxious attachment and depressive symptoms in partners were significantly positively associated with depressive symptoms Findings underscore the importance of considering couples-based approaches to supporting the transition to parenthood and developing the necessary self and relationship skills to manage attachment needs and relationship challenges.


Serum levels of 25-hydroxyvitamin D and survival in Norwegian patients with cancer of breast, colon, lung, and lymphoma: a population-based study.
We investigated the association between serum levels of 25-hydroxyvitamin D (25-OHD) and risk of death in Norwegian cancer patients. The study population was 658 patients with cancers of the breast (n = 251), colon (n = 52), lung (n = 210), and lymphoma (n = 145), obtained from JANUS, a population-based serum bank in Norway. Serum samples were collected within 90 days of cancer diagnosis and were analyzed for 25-OHD. Patients were diagnosed during 1984-2004 and were followed for death throughout 2008. We used Cox regression models to assess the relationship between serum 25-OHD and risk of death. Three hundred and ninety-nine patients died during follow-up, of whom 343 (86%) died from cancer. Adjusted for sex, age at diagnosis, and season of blood sampling, patients with 25-OHD levels below 46 nmol/L at diagnosis experienced shorter survival. Compared to patients in the lowest quartile of serum 25-OHD, the risk of cancer death among patients in the highest quartile was significantly reduced (HR 0.36 95% CI 0.27, 0.51). The estimated change in risk of cancer death was most pronounced between the first and the second quartile. The associations between 25-OHD levels and survival were observed for all four cancers. Higher circulating serum levels of 25-OHD were positively associated with the survival for cancers of the breast, colon, lung, and lymphoma.


[Changes in hemostasis in patients with cancer of the stomach].
A hemocoagulation study of patients with stage I-IV stomach tumors revealed hypercoagulemia and inhibited fibrinolysis regarded as a prethrombotic state. The changes were more pronounced in extensive tumor process (stage IV). Some patients showed initial signs of thrombohemorrhagic syndrome.


Antioxidant effect of Kimchi supplemented with Jeju citrus concentrate and its antiobesity effect on 3T3-L1 adipocytes.
Citrus is cultivated throughout Jeju Island and is thought to possess some medicinal properties. Citrus concentrate is the most extensively utilized form of citrus in the food industry. In this study, antioxidant and antiobesity effects of Kimchi supplemented with citrus concentrate were investigated. Prepared Kimchi was infused with 7% citrus concentrate (CK) and freeze-dried for analysis. Normal Kimchi (NK) without citrus concentrate was utilized as a control. Total phenol content (TPC), total flavonoid content (TFC), and antioxidant activities were examined. Cytotoxicity, intracellular triglycerides (TG), and total cholesterol (TC) levels in 3T3-L1 adipocytes were also measured. Additionally, the inhibitory effects on lipid accumulation were trialed by measuring the oil-red O (ORO)-stained cells. TPC, TFC, and antioxidant activities of CK were significantly higher than those of NK (p < .05). CK showed less cytotoxicity and attenuated the lipid accumulation at all concentrations by reducing TG and TC levels compared to NK. The inhibitory effect of CK on lipid accumulation was observed via reducing ORO-stained lipid droplets. Consequently, the antioxidant and antiobesity effects of CK were revealed in vitro. Furthermore, the addition of citrus may provide competitive price due to low production costs as well as health functionality.


The effect of vigorous treadmill exercise on adipose tissue development in the Zucker rat.
Four-week-old male lean and obese Zucker rats were subjected to intense daily exercise for a 10-week period. The exercise regimen used (running 6 days/week for 90 min/day on a treadmill at 1.3 Km/h at an 8 per cent grade) was designed to maximize the amount of exercise performed. Lean and obese runners (LR and OR) gained significantly less weight than sedentary controls (LS and OS). Food intake was lower in LR and unchanged in OR compared with control animals. Exercise increased adrenal weight in runners of both phenotypes. Gastrocnemius muscle weight was significantly higher in OR compared to OS. Despite the intense exercise regimen, carcass fat of OR was reduced only 12 per cent versus OS. In contrast, exercise decreased carcass fat by 32 per cent in LR versus LS. This decrease in body fat of LR was due to smaller adipocytes. Exercise did not affect adipocyte size in obese rats. However, OR had fewer carcass adipocytes. These results indicate that exercise had substantially different effects on adipose tissue cellularity of lean and obese rats. The results of the present study indicate that a program of intense treadmill exercise initiated immediately post weaning only modestly reduced adipose tissue growth in obese Zucker rats. Furthermore, it did not normalize body composition.


Neuropeptide Y is a potent vasoconstrictor and a cardiodepressant in rat.
Neuropeptide Y (NPY) is contained in and coreleased with norepinephrine (NE) from sympathetic nerves innervating vascular and cardiac tissues. The effects of NPY infusion on systemic hemodynamics and cardiac performance were compared with those of NE in conscious and pentobarbital sodium-anesthetized rats. A 10-min infusion of NPY (2 nmol.kg-1.min-1) decreased cardiac index (CI) 20% and stroke volume index (SVI) 9% with increases of 20% in mean arterial pressure (MAP) and 48% in total peripheral resistance (TPR). Conversely, NE (1.0 microgram.kg-1.min-1) increased SVI 14%, MAP 29%, and TRP 26%, with no change in CI. Heart rates decreased similarly (approximately 60 beats/min) but only NE-induced bradycardia was reversible by methylatropine nitrate. In anesthetized rats NPY (0.1 nmol.kg-1.min-1) increased left ventricular end-diastolic pressure (LVEDP) 20 +/- 10 mmHg (means +/- SD, n = 7) and decreased dP/dt by 8 +/- 6%. NE (0.07 microgram.kg-1.min-1) produced an equivalent pressor response, however, dP/dt rose 22 +/- 10% whereas LVEDP increased significantly less than with NPY. Thus NPY is a potent vasoconstrictor exerting similar effects to NE on MAP and TPR but, unlike NE, possesses negative inotropic and chronotropic activity.


[The parallelisms in of sound signal of domestic sheep and Northern fur seals].
The parallelisms in communicative behavior of domestic sheep and Northern fur seals within a herd are accompanied by parallelisms in parameters of sound signal, the calling scream. This signal ensures ties between babies and their mothers at a long distance. The basis of parallelisms is formed by amplitude modulation at two levels: the one being a direct amplitude modulation of the carrier frequency and the other--modulation of the carrier frequency oscillation. Parallelisms in the signal oscillatory process result in corresponding parallelisms in the structure of its frequency spectrum.


Association between ethnic background and COVID-19 morbidity, mortality and vaccination in England: a multistate cohort analysis using the UK Biobank.
Despite growing evidence suggesting increased COVID-19 mortality among people from ethnic minorities, little is known about milder forms of SARS-CoV-2 infection. We sought to explore the association between ethnic background and the probability of testing, testing positive, hospitalisation, COVID-19 mortality and vaccination uptake. A multistate cohort analysis. Participants were followed between 8 April 2020 and 30 September 2021. The UK Biobank, which stores medical data on around half a million people who were recruited between 2006 and 2010. 405 541 subjects were eligible for analysis, limited to UK Biobank participants living in England. 23 891 (6%) of participants were non-white. The associations between ethnic background and testing, testing positive, hospitalisation and COVID-19 mortality were studied using multistate survival analyses. The association with single and double-dose vaccination was also modelled. Multistate models adjusted for age, sex and socioeconomic deprivation were fitted to estimate adjusted HRs (aHR) for each of the multistate transitions. 18 172 (4.5%) individuals tested positive, 3285 (0.8%) tested negative and then positive, 1490 (6.9% of those tested positive) were hospitalised, and 129 (0.6%) tested positive at the moment of hospital admission (ie, direct hospitalisation). Finally, 662 (17.4%) died after admission. Compared with white participants, Asian participants had an increased risk of negative to positive transition (aHR 1.24 (95% CI 1.02 to 1.52)), testing positive (95% CI 1.44 (1.33 to 1.55)) and direct hospitalisation (1.61 (95% CI 1.28 to 2.03)). Black participants had an increased risk of hospitalisation following a positive test (1.71 (95% CI 1.29 to 2.27)) and direct hospitalisation (1.90 (95% CI 1.51 to 2.39)). Although not the case for Asians (aHR 1.00 (95% CI 0.98 to 1.02)), black participants had a reduced vaccination probability (0.63 (95% CI 0.62 to 0.65)). In contrast, Chinese participants had a reduced risk of testing negative (aHR 0.64 (95% CI 0.57 to 0.73)), of testing positive (0.40 (95% CI 0.28 to 0.57)) and of vaccination (0.78 (95% CI 0.74 to 0.83)). We identified inequities in testing, vaccination and COVID-19 outcomes according to ethnicity in England. Compared with whites, Asian participants had increased risks of infection and admission, and black participants had almost double hospitalisation risk, and a 40% lower vaccine uptake.


Intravenous catheter-associated fungemia due to Candida rugosa.
We report a case of intravenous catheter-associated fungemia caused by Candida rugosa; this is the first report of such an infection in a human. Multiple cultures of blood taken over a 24-h period and of the intravenous catheter tip were positive for this unusual isolate. The patient was treated with intravenous amphotericin B and made an uneventful recovery. Intravenous cannulae and other intravascular devices are well recognized as potential sites of intravascular infection by a variety of microorganisms, including several Candida species; however, fungemia caused by C. rugosa has not been reported.


Costs and quality of life of small-incision open cholecystectomy and laparoscopic cholecystectomy - an expertise-based randomised controlled trial.
Health care providers need solid evidence based data on cost differences between alternative surgical procedures for common surgical disorders. We aimed to compare small-incision open cholecystectomy (SIOC) and laparoscopic cholecystectomy (LC) concerning costs and health-related quality of life using data from an expertise-based randomised controlled trial. Patients scheduled for cholecystectomy were assigned to undergo LC or SIOC performed by surgeons in two different expert groups. Total costs were calculated in USD. Reusable instruments were assumed for the cost analysis. Quality of life was measured using the EuroQol 5-D 3-L (EQ 5-D-3L), at five postoperative time points and calculated to Area Under Curve (AUC) for 1 year postoperatively. Two hospitals participated in the trial, which included both emergency and elective surgery. Of 477 patients that underwent a cholecystectomy during the study period, 355 (74.9%) were randomised and 323 analysed, 172 LC and 151 SIOC patients. Both direct and total costs were less for SIOC than for LC patients. The total costs were 5429 (4293-6932) USD for LC and 4636 (3905-5746) USD for SIOC, P = 0.001. The quality of life index did not differ between the LC and SIOC groups at any time. Median values (25th and 75th percentiles (p25-p75)) for AUC at 1 year were as follows: 349 (337-351) for LC and 349 (338-350) for SIOC. In this expertise-based randomised controlled trial LC was a more costly procedure and quality of life did not differ after SIOC and LC. (ClinicalTrials.gov Identifier: NCT00370344, August 30, 2006).


Percutaneous endoscopic approach for highly migrated intracanal disc herniations by foraminoplastic technique using rigid working channel endoscope.
A retrospective analysis of 59 patients operated for excision of soft highly migrated intracanal lumbar disc herniations by percutaneous endoscopic foraminoplasty. To describe a safe and effective percutaneous endoscopic technique for removal of migrated herniations and report the results on the basis of modified MacNab criteria. Migrated herniations pose a great challenge even for experienced endoscopic surgeons. These herniations are hidden from the endoscopic view by anatomic barriers like hypertrophied facet, inferior pedicle and foraminal ligaments rendering percutaneous endoscopic transforaminal lumbar discectomy (PELD) by conventional approach, difficult with high failure rate. Foraminoplasty, which means enlargement of foramen by undercutting ventral part of superior-facet, upper border of inferior pedicle along with ablation of foraminal ligament, can help us to address this issue. Fifty-nine patients with soft highly migrated herniations who underwent PELD with foraminoplasty under local anesthesia from January 2002 to June 2006 were analyzed retrospectively. Patients were evaluated by postoperative Visual Analog Scale for leg pain and Oswestry Disability Index scores. Outcomes were graded according to modified MacNab criteria. Mean follow-up was 25.4 months. Mean visual analog scale score for radicular pain improved from 8.01 to 1.56, and mean Oswestry disability Index improved from 61.6 to 10.76. Based on modified MacNab criteria, 91.4% of patients experienced satisfactory outcome. Three patients had persistent leg pain after surgery. One patient underwent a repeat-PELD on next day and the other after 1 month. Both were relieved of symptoms. Third patient was subjected to open discectomy after 25 weeks from the first operation and showed improvement. Two patients had recurrent herniation at same level after 6 months; 1 patient underwent repeat PELD, and the other underwent open discectomy. Both patients had good results. Foraminoplastic-PELD is safe and effective procedure for surgical treatment of soft migrated herniations. The results are comparable to results of open discectomy.


Molecular architecture of the "stressosome," a signal integration and transduction hub.
A commonly used strategy by microorganisms to survive multiple stresses involves a signal transduction cascade that increases the expression of stress-responsive genes. Stress signals can be integrated by a multiprotein signaling hub that responds to various signals to effect a single outcome. We obtained a medium-resolution cryo-electron microscopy reconstruction of the 1.8-megadalton "stressosome" from Bacillus subtilis. Fitting known crystal structures of components into this reconstruction gave a pseudoatomic structure, which had a virus capsid-like core with sensory extensions. We suggest that the different sensory extensions respond to different signals, whereas the conserved domains in the core integrate the varied signals. The architecture of the stressosome provides the potential for cooperativity, suggesting that the response could be tuned dependent on the magnitude of chemophysical insult.


High-resolution 3D whole-heart coronary MRA: a study on the combination of data acquisition in multiple breath-holds and 1D residual respiratory motion compensation.
To study a scan protocol for coronary magnetic resonance angiography based on multiple breath-holds featuring 1D motion compensation and to compare the resulting image quality to a navigator-gated free-breathing acquisition. Image reconstruction was performed using L1 regularized iterative SENSE. The effects of respiratory motion on the Cartesian sampling scheme were minimized by performing data acquisition in multiple breath-holds. During the scan, repetitive readouts through a k-space center were used to detect and correct the respiratory displacement of the heart by exploiting the self-navigation principle in image reconstruction. In vivo experiments were performed in nine healthy volunteers and the resulting image quality was compared to a navigator-gated reference in terms of vessel length and sharpness. Acquisition in breath-hold is an effective method to reduce the scan time by more than 30% compared to the navigator-gated reference. Although an equivalent mean image quality with respect to the reference was achieved with the proposed method, the 1D motion compensation did not work equally well in all cases. In general, the image quality scaled with the robustness of the motion compensation. Nevertheless, the featured setup provides a positive basis for future extension with more advanced motion compensation methods.


EGF and bFGF pre-treatment enhances neural specification and the response to neuronal commitment of MIAMI cells.
Multipotent mesenchymal stromal cells raise great interest for regenerative medicine studies. Some MSC subpopulations have the potential to undergo neural differentiation, including marrow isolated adult multilineage inducible (MIAMI) cells, which differentiate into neuron-like cells in a multi-step neurotrophin 3-dependent manner. Epidermal and basic fibroblast growth factors are often used in neuronal differentiation protocols for MSCs, but with a limited understanding of their role. In this study, we thoroughly assessed for the first time the capacity of these factors to enhance the neuronal differentiation of MSCs. We have characterized MIAMI cell neuronal differentiation program in terms of stem cell molecule expression, cell cycle modifications, acquisition of a neuronal morphology and expression of neural and neuronal molecules in the absence and presence of an EGF-bFGF pre-treatment. EGF-bFGF pre-treatment down-regulated the expression of stemness markers Oct4A, Notch1 and Hes5, whereas neural/neuronal molecules Nestin, Pax6, Ngn2 and the neurotrophin receptor tyrosine kinase 1 and 3 were up-regulated. During differentiation, a sustained Erk phosphorylation in response to NT3 was observed, cells began to exit from the cell cycle and exhibit increased neurite-like extensions. In addition, neuronal β3-tubulin and neurofilament expression was increased; an effect mediated via the Erk pathway. A slight pre-oligodendrocyte engagement was noted, and no default neurotransmitter phenotype was observed. Overall, mesodermal markers were unaffected or decreased, while neurogenic/adipogenic PPARγ2 was increased. EGF and bFGF pre-treatment enhances neural specification and the response to neuronal commitment of MIAMI cells, further increasing their potential use in adult cell therapy of the nervous system.


Biomaterials for orthopedics: a roughness analysis by atomic force microscopy.
We conducted an AFM analysis of roughness on 7 materials widely used in bone reconstruction. Roughness was evaluated by measuring Root Mean Square (RMS) values and RMS/average height (AH) ratio, in different dimensional ranges, varying from 100 microns square to a few hundreds of nanometers. The results showed that Titanium presented a lower roughness than the other materials analyzed, frequently reaching statistical significance. On the contrary, bioactive materials, such as hydroxyapatite (HA) and bioactive glasses, demonstrated an overall higher roughness. In particular, this study focuses attention on AP40 and especially RKKP, which proved to have a significant higher roughness at low dimensional ranges. This determines a large increase in surface area, which is strongly connected with osteoblast adhesion and growth and to protein absorption. Therefore, the biointegration properties of bioactive glasses can also be given as answer in terms of surface structures in which chemical composition can influence directly the biological system (e.g. with chemical exchanges and development of specific surface electrical charge) and indirectly, via the properties induced on tribological behavior that expresses itself during the smoothing of the surfaces. We also test two new bioactive glasses, RBP1 and RBP2, with a chemical composition similar to AP40, but with some significant small additions and substitutions of components, in order to make preliminary considerations on their potential role in orthopedics.


Galanin expression in a murine model of allergic contact dermatitis.
Galanin is a neuropeptide widely distributed in the nervous system. The expression of galanin was investigated in murine contact allergy using immunohistochemistry, radioimmunoassay and in situ hybridization. Female BALB/c mice were sensitized with oxazolone and 6 days later challenged on the dorsal surface of ears, while control mice received vehicle. After 24 h, one ear was processed for immunostaining using a biotinylated fluorescence technique, while the other ear was frozen and processed for radioimmunoassay or in situ hybridization. Galanin immunoreactive nerve fibres were more numerous (p < 0.01) in the eczematous compared with control ears. Double-staining with antibody to the nerve fibre marker PGP (protein gene product) 9.5 revealed colocalization of PGP 9.5 and galanin in nerve fibres. Radioimmunoassay demonstrated a decrease (p < 0.04) in galanin concentration in eczematous compared with control ears. Our results suggest a role for galanin in murine contact allergy.


Expression of metabolism-related proteins in triple-negative breast cancer.
To investigate the dominant metabolic type of triple-negative breast cancer (TNBC) and evaluate its clinical implication through analysis of protein expression related to glycolysis, glutaminolysis, and mitochondrial oxidative phosphorylation. Tissue samples from 129 patients with TNBC who underwent mastectomy due to invasive breast cancer from 2000 to 2005 were prepared for tissue microarray. By immunohistochemical staining of the tissue microarrays, the markers of glycolysis-related proteins (Glut-1, CAIX, MCT4), glutaminolysis-related proteins (GLS1, GDH, ASCT2), and mitochondrial enzymes (ATP synthase, SDHA and SDHB) were analyzed. Based on the results, the metabolic phenotypes were defined based on positivity for more than two of three markers for each phenotype as follows: glycolysis type (Glut-1, CAIX and MCT4), glutaminolysis type (GLS1, GDH and ASCT2) and mitochondrial type (ATP synthase, SDHA and SDHB). The percentages of samples with metabolic phenotypes of tumor and stroma of TNBC were as follows: for tumor, mitochondrial type (85.3%)>glutaminolysis type (67.4%)>glycolysis type (63.0%); and for stroma, glutaminolysis type (37.2%)>glycolysis type (16.3%)>mitochondrial type (14.0%). The most common metabolic phenotype of TNBC was glycolysis type for basal-like type and non-glycolysis type for non-basal-like type (p=0.047). The correlation between glutaminolysis and mitochondrial type was statistically significant in both tumor and stroma (p<0.001). In conclusion, tumor cells of TNBC express glycolysis and mitochondrial metabolism-related proteins. Glycolysis type is the most common phenotype of basal-like type, and reversely, non-glycolysis type is the most common phenotype of non basal-like type.


Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis.
We conducted a systematic review of the literature and network meta-analysis (NMA) to compare the relative effectiveness of antibiotic treatments for Clostridioides (Clostridium) difficile infection (CDI) including vancomycin (VCM), metronidazole (MTZ) and fidaxomicin (FDX). Eligible studies were randomised controlled trials (RCTs) including adults with any severity of CDI that was treated with VCM, MTZ or FDX. The NMA was performed using a Bayesian framework, using a fixed-effects model. The searches identified seven publications for inclusion, which provided five RCTs for VCM versus MTZ, and three RCTs for FDX versus VCM. The NMA showed that for clinical cure rate, there was no difference for FDX versus VCM, and there was a significant difference in favour of FDX versus MTZ (odds ratio [OR]: 1.77; 95% credible interval [CrI] 1.11, 2.83]). For recurrence rate, there was a significant difference in favour of FDX versus both VCM (OR: 0.50; 95% CrI: 0.37, 0.68) and MTZ (OR: 0.44; 95% CrI: 0.27, 0.72). For sustained cure (clinical cure without recurrence), there was a significant difference in favour of FDX versus VCM (OR: 1.61; 95% CrI: 1.27, 2.05) and MTZ (OR: 2.39; 95% CrI: 1.65, 3.47). These findings suggest that FDX and VCM are effective first-line treatments for mild or moderate CDI, whereas MTZ is not, and FDX may be more effective at preventing CDI recurrence than VCM.


Assessing efficacy by measuring CD(4) counts and quality of life of AIDS patients treated with ritonavir, AZT and 3TC.
Lamivudine and zidovudine are proving to be an important antiretroviral combination against HIV that is superior to monotherapy. Recently, with the appearance of protease inhibitors, ritonavir has been shown to be a powerful drug when used in combination with reverse transcriptase inhibitors. The objective of this study was to observe the efficacy, adverse events, and changes in the quality of life of AIDS patients receiving treatment for the first time using AZT, 3TC and ritonavir as combination therapy. We selected 36 patients diagnosed with AIDS due to opportunistic infections and evaluated them by assessing their score on quality of life scales (Karnofsky, uniscale - Quality of Life, and Quality of Life Scale), T CD(4) and CD(8) lymphocyte counts, bodyweight and symptoms during a 6 month period. Assessments were made at 2 month intervals. One patient was excluded from the trial, therefore, 35 were assessed during 6 months. Bodyweight increased an average of 7.2%, CD(4) increased 260 cells/mm(3) and CD(8) increased 198 cells/mm(3). The Karnofsky and uniscale QOL scales reached 100% on the fourth visit. The Quality of Life Scale showed an important increase during this study from 5.5+/-2.3 to 9.7+/-0.5. Adverse events were observed in 25.0% of the patients, most being slight. One patient had to stop taking ritonavir due to nausea and vomiting. We conclude that AZT, 3TC, and ritonavir restored the quality of life for the AIDS patients studied in terms of psychosocial aspects and overall health conditions during 6 months of treatment. The adverse events were probably related to ritonavir, but they were slight and disappeared after 2 weeks. There was a significant increase in the average number of CD(4) lymphocytes during 6 months of treatment.


Potential risk of repeated nasal vaccination that induces allergic reaction with mucosal IgE and airway eosinophilic infiltration in cynomolgus macaques infected with H5N1 highly pathogenic avian influenza virus.
The efficacy and detrimental effect of mucosal vaccination with an inactivated influenza vaccine were examined in a macaque model by intranasal administration with small amounts of inactivated whole virus particles and challenge by a human-derived H5N1 highly pathogenic avian influenza virus infection. Repeated nasal inoculation with the whole particle vaccine of an inactivated virus, A/duck/Hokkaido/Vac-3/2007 (H5N1) (Vac-3), induced antigen-specific IgA and IgG antibody production in nasal swabs and plasma. Vac-3-specific IgE production was also found in the nasal swabs. Nasal vaccination with Vac-3 induced broader cross-clade neutralization activity than did subcutaneous vaccination. After challenge infection, repeated nasal vaccination almost completely prevented the propagation of virus in the upper and lower airways and protected cynomolgus macaques from viral pneumonia by induction of IgA-producing B cells in the lungs. On the other hand, eosinophil clusters were observed in the lungs of vaccinated macaques. Although Vac-3-specific IgE antibody and IL-13 levels were decreased after infection compared to those before infection and no anaphylaxis in vaccinated macaques was detected after challenge infection, our results suggest that we have to pay attention to potential allergic responses at repeated nasal vaccination, especially in people who have an airway allergy.


The forecasting power of the microbiome.
Microorganisms are informative biological integrators of past and present environmental abiotic and biotic conditions. At the same time, they are directly involved in ecosystem processes. Unfortunately, the complexity of microbial communities has so far resulted in most studies being descriptive. Here, we suggest that signals in the microbiome data can be used to forecast future ecosystem processes. The combination of omics with various statistical learning approaches, selected based on accuracy-interpretability and bias-variance trade-offs, will be key to attain this goal, as exemplified by recent studies. The time is ripe for microbial ecologists to fully exploit the forecasting power of microbiomes.


Stage IV Pancreatic Cancer Patient Treated With FOLFIRINOX Combined With Oral Methioninase: A Highly-Rare Case With Long-term Stable Disease.
Pancreatic cancer is one of the most recalcitrant cancers, and more effective therapy is needed. Pre-clinical studies have shown that patient-derived orthotopic xenograft (PDOX) mouse models of pancreatic cancer are effectively treated with oral recombinant methioninase (o-rMETase). A 62-year-old woman diagnosed with stage IV pancreatic cancer was treated with the combination of 5-fluorouracil/leucovorin, irinotecan, and oxaliplatinum (FOLFIRINOX) every two weeks and o-rMETase twice a day as a supplement. The patient was also on a low-methionine diet. Disease progression was monitored by CA19-9 and computed tomography. The patient initially responded to FOLFIRINOX, shown by a great reduction in CA19-9 levels, with tumor shrinkage shown by computed tomography. The patient began taking o-rMETase and went on a low-methionine diet one year after diagnosis which she has maintained without side effects for 7 months. The patient's CA19-9 level and tumor size remain stable 19 months after diagnosis. The patient is alive and has maintained a high performance status. Historical data show that less than 5% of stage IV pancreatic-cancer patients on FOLFIRINOX have stable disease 1.5 years after diagnosis. The combination of o-rMETase and FOLFIRINOX may be synergistic in stage IV pancreatic cancer.


Sulfur concentration in diets containing corn, soybean meal, and distillers dried grains with solubles does not affect feed preference or growth performance of weanling or growing-finishing pigs.
Four experiments were conducted to investigate the effects of distillers dried grains with solubles (DDGS) and dietary S on feed preference and performance of pigs. In a 10-d feed preference experiment (Exp. 1), 48 barrows (20.1 ± 2.2 kg of BW) were randomly allotted to 3 treatment groups, with 8 replicate pens per treatment and 2 pigs per pen. A control diet based on corn and soybean meal, a DDGS diet containing 20% DDGS, and a DDGS-sulfur (DDGS-S) diet were prepared. The DDGS-S diet was similar to the DDGS diet with the exception that 0.74% CaSO(4) was added to the diet. Two diets were provided in separate feeders in each pen: 1) the control diet and the DDGS diet, 2) the control diet and the DDGS-S diet, or 3) the DDGS diet and the DDGS-S diet. Preference for the DDGS diet and the DDGS-S diet vs. the control diet was 35.2 and 32.6%, respectively (P < 0.05), but there was no difference between the DDGS diet and the DDGS-S diet. In Exp. 2, a total of 90 barrows (10.3 ± 1.4 kg of BW) were allotted to 3 treatments, with 10 replicate pens and 3 pigs per pen, and were fed the diets used in Exp. 1 for 28 d, but only 1 diet was provided per pen. Pigs fed the control diet gained more BW (497 vs. 423 and 416 g/d; P < 0.05) and had greater G:F (0.540 vs. 0.471 and 0.455; P < 0.05) than pigs fed the DDGS or the DDGS-S diet, but no differences between the DDGS and the DDGS-S diets were observed. In a 10-d feed preference experiment (Exp. 3), 30 barrows (49.6 ± 2.3 kg of BW) were allotted to 3 treatment groups, with 10 replicates per group. The experimental procedures were the same as in Exp. 1, except that 30% DDGS was included in the DDGS and DDGS-S diets and 1.10% CaSO(4) was added to the DDGS-S diet. Feed preference for the DDGS and the DDGS-S diets, compared with the control diet, was 29.8 and 32.9%, respectively (P < 0.01), but there was no difference between the DDGS and the DDGS-S diets. In Exp. 4, a total of 120 barrows (34.2 ± 2.3 kg of BW) were fed grower diets for 42 d and finisher diets for 42 d. Diets were formulated as in Exp. 3. Pigs on the control diets gained more BW (1,021 vs. 912 and 907 g/d; P < 0.05) and had greater G:F (0.335 vs. 0.316 and 0.307; P < 0.05) than pigs fed the DDGS or DDGS-S diet, respectively, but no differences between pigs fed the DDGS and the DDGS-S diets were observed. In conclusion, dietary S concentration does not negatively affect feed preference, feed intake, or growth performance of weanling or growing-finishing pigs fed diets based on corn, soybean meal, and DDGS.


Effect of adjuvant chemotherapy after pancreatectomy in patients with node-negative pancreatic cancer: target trial emulation.
The effect of adjuvant therapy in node-negative pancreatic cancer is uncertain. The aim of this study was to estimate the effect of adjuvant chemotherapy on survival after surgery for pancreatic cancer in patients with node-negative (pN0) and node-positive (pN+) disease using target trial emulation. This was an observational cohort study emulating a hypothetical RCT by the clone-censor-weight approach using population-based Danish healthcare registries. The study included Danish patients undergoing curative-intent surgery for pancreatic cancer during 2008-2021, who were discharged alive no more than 4 weeks after surgery. At the time of discharge after surgery, the data for each patient were duplicated; one copy was assigned to the adjuvant chemotherapy strategy and the other to the no adjuvant chemotherapy strategy of the hypothetical trial. Copies were censored when the assigned treatment was no longer compatible with the observed treatment. To account for informative censoring, uncensored patients were weighted according to measured confounders. The primary outcomes were absolute difference in 2-year survival and median overall survival, comparing adjuvant with no adjuvant chemotherapy. Some 424 patients with pN0 and 953 with pN+ disease were included. Of these, 62.0 and 74.6% respectively initiated adjuvant chemotherapy within the 8-week grace period. Among patients with pN0 tumours, the difference in 2-year survival between those with and without adjuvant therapy was -2.2 (95% c.i. -11.8 to 7.4)%. In those with pN+ disease, the difference in 2-year survival was 9.9 (1.6 to 18.1)%. Median overall survival was 24.9 (i.q.r. 12.8-49.4) and 15.0 (8.0-34.0) months for patients having adjuvant and no adjuvant therapy respectively. In a target trial emulation using observational data, adjuvant chemotherapy did not improve survival after surgery for node-negative pancreatic cancer.


A DIFFUSE-INTERFACE APPROACH FOR MODELING TRANSPORT, DIFFUSION AND ADSORPTION/DESORPTION OF MATERIAL QUANTITIES ON A DEFORMABLE INTERFACE.
A method is presented to solve two-phase problems involving a material quantity on an interface. The interface can be advected, stretched, and change topology, and material can be adsorbed to or desorbed from it. The method is based on the use of a diffuse interface framework, which allows a simple implementation using standard finite-difference or finite-element techniques. Here, finite-difference methods on a block-structured adaptive grid are used, and the resulting equations are solved using a non-linear multigrid method. Interfacial flow with soluble surfactants is used as an example of the application of the method, and several test cases are presented demonstrating its accuracy and convergence.


Elephants in Nepal: Correlating disease, tourism, and welfare.
Asian elephants and humans have long shared their lives, but recent changes in human perspectives on animal use have created ripples through the small country of Nepal. Captive elephants are caught in the crossfire between local communities, elephant owners, mahouts, and NGOs in debates over their treatment, health, welfare and use in tourism. In addition, zoonotic disease, natural disasters and political strife affect the lives of captive elephants and mahouts. For example, during the COVID-19 pandemic, elephants, caregivers and owners found themselves facing income loss, decreased welfare from housing and husbandry issues, and food shortages. Many owners sold elephants, fired mahouts, and "quit" the tourism industry. Others sought help from outside organizations, community members, and governmental agencies to retain ownership of what they viewed as valuable commodities. NGOs and grassroots organizations assisted in the hopes of keeping elephants in Nepal, thus preventing them from long, treacherous walks across the border and into situations where they might face further welfare decreases. This article combines elephant stable visits and interviews with mahouts, owners, NGO, and government staff between January 2019 and December 2021. It highlights the ongoing health and welfare challenges faced by elephants and mahouts in Nepal.


Unfavorable cortical hypertrophy potentially predisposes to periprosthetic "axe splitter" fracture in a collarless polished curved triple-tapered cemented stem: The time-dependent radiographic change in five SC-stem cases.
The periprosthetic fracture of cemented polished tapered stems is occasionally called a "unique" or "axe splitter" fracture. However, there has been insufficient evidence regarding the association between the radiographic findings prior to incidence and this cumbersome fracture. To determine if there are any radiographic interpretations associated with this fracture pattern, we report the five SC-stem cases with total hip arthroplasty. We investigate the patient characteristics and serial radiographs of five fracture cases and evaluate the time-dependent specific radiographical changes around the stem between pre-arthroplasty and fracture. Fractures developed at 3.5-6.4 years after surgery with low-grade injury or with no particular incentive. Femoral cortical hypertrophy at the distal medial side around the stem was observed in all cases before the development of fractures, at 2-6 years after primary surgery. The duration between cortical hypertrophy appearance to the development of fracture was 0.4-3.1 years. The appearance of this zone-specific cortical hypertrophy might play a key role in the occurrence of periprosthetic fractures. Further studies with larger sample sizes should be conducted to elucidate this eccentric periprosthetic fracture.


The optimum spine.
System theory is used to describe the mechanism of the lumbar spine. The role of the spine in vertebrate evolution is presented. The importance of the intervertebral joint for the survival of the species is shown to be crucial. The mechanical behavior of the joint is derived, and from this the corresponding spinal motion and muscular responses is calculated. It is shown that physiologic behavior implies that the stress at the intervertebral joints is equalized and minimized. From this simple condition, the motion of the spine in the sagittal plane is calculated. From the analysis of sagittal plane motion together with a knowledge of the energy transfer through the intervertebral joint, a new theory of locomotion is derived. This theory of locomotion differs in important respects from current theories, but nevertheless explains available experimental data. This unified theory of the function of the human spine permits the determination of the level of safe loads that can be lifted and transported. It predicts the conditions of load transfer through a joint. It proposes a new approach to the mechanism of arthritis and to the repair of fractures.


Coronary Artery Bypass Surgery in Diffuse Advanced Coronary Artery Disease: 1-Year Clinical and Angiographic Results.
Proper treatment of patients with diffuse, severe coronary artery disease (CAD) is a challenge due to its complexity. Thus, data on the outcomes after coronary artery bypass graft (CABG) in this population is scarce. In this study, we aimed to determine the impact of CABG on the clinical and functional status, as well as graft patency in those individuals. Patients with severe and diffuse CAD who underwent incomplete CABG due to complex anatomy or extensive distal coronary involvement were evaluated preoperatively and 1 year after surgery. Postoperative coronary angiography was performed to evaluate graft patency. Graft occlusion was defined as the complete absence of opacification of the target vessel. Stratified analysis of graft occlusion was performed by graft type and territories, defined as left anterior descending artery (LAD), the left circumflex branch, and the right coronary artery territories; the latter two, grouped, were further classified as non-LAD territory. A total of 57 patients were included, in whom 131 grafts were placed. There was a significant improvement in Canadian Cardiovascular Society angina symptom severity (Z = -6.1; p < 0.001) and maximum oxygen uptake (p < 0.001), with a corresponding decrease in the use of long-acting nitrates (p < 0.001). The overall graft occlusion rate was 19.1%, with no significant difference between LAD and non-LAD territories (p = 0.08). However, a significantly lower occlusion rate was noted for the internal mammary artery (IMA) grafts when compared with saphenous vein grafts (p = 0.01), though this difference was only significant in the LAD territory (p = 0.04). Overall, the use of venous graft was the only predictor occlusion at 1 year (odds ratio: 4.03; p = 0.016). In patients with diffuse CAD, incomplete CABG surgery resulted in a significant clinical improvement, with acceptable graft occlusion rates at 1 year, particularly for IMA grafts to the LAD territory.


Overlapping LQT1 and LQT2 phenotype in a patient with long QT syndrome associated with loss-of-function variations in KCNQ1 and KCNH2.
Long QT syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and potentially life-threatening arrhythmias. Mutations in 12 different genes have been associated with LQTS. Here we describe a patient with LQTS who has a mutation in KCNQ1 as well as a polymorphism in KCNH2. The proband (MMRL0362), a 32-year-old female, exhibited multiple ventricular extrasystoles and one syncope. Her ECG (QT interval corrected for heart rate (QTc) = 518ms) showed an LQT2 morphology in leads V4-V6 and LQT1 morphology in leads V1-V2. Genomic DNA was isolated from lymphocytes. All exons and intron borders of 7 LQTS susceptibility genes were amplified and sequenced. Variations were detected predicting a novel missense mutation (V110I) in KCNQ1, as well as a common polymorphism in KCNH2 (K897T). We expressed wild-type (WT) or V110I Kv7.1 channels in CHO-K1 cells cotransfected with KCNE1 and performed patch-clamp analysis. In addition, WT or K897T Kv11.1 were also studied by patch clamp. Current-voltage (I-V) relations for V110I showed a significant reduction in both developing and tail current densities compared with WT at potentials >+20 mV (p < 0.05; n = 8 cells, each group), suggesting a reduction in IKs currents. K897T- Kv11.1 channels displayed a significantly reduced tail current density compared with WT-Kv11.1 at potentials >+10 mV. Interestingly, channel availability assessed using a triple-pulse protocol was slightly greater for K897T compared with WT (V0.5 = -53.1 ± 1.13 mV and -60.7 ± 1.15 mV for K897T and WT, respectively; p < 0.05). Comparison of the fully activated I-V revealed no difference in the rectification properties between WT and K897T channels. We report a patient with a loss-of-function mutation in KCNQ1 and a loss-of-function polymorphism in KCNH2. Our results suggest that a reduction of both IKr and IKs underlies the combined LQT1 and LQT2 phenotype observed in this patient.


Chemically tuned linear energy transfer dependent quenching in a deformable, radiochromic 3D dosimeter.
Most solid-state detectors, including 3D dosimeters, show lower signal in the Bragg peak than expected, a process termed quenching. The purpose of this study was to investigate how variation in chemical composition of a recently developed radiochromic, silicone-based 3D dosimeter influences the observed quenching in proton beams. The dependency of dose response on linear energy transfer, as calculated through Monte Carlo simulations of the dosimeter, was investigated in 60 MeV proton beams. We found that the amount of quenching varied with the chemical composition: peak-to-plateau ratios (1 cm into the plateau) ranged from 2.2 to 3.4, compared to 4.3 using an ionization chamber. The dose response, and thereby the quenching, was predominantly influenced by the curing agent concentration, which determined the dosimeter's deformation properties. The dose response was found to be linear at all depths. All chemical compositions of the dosimeter showed dose-rate dependency; however this was not dependent on the linear energy transfer. Track-structure theory was used to explain the observed quenching effects. In conclusion, this study shows that the silicone-based dosimeter has potential for use in measuring 3D-dose-distributions from proton beams.


[A study on suicide in Asturias: increase of the frequency in the last two decades].
The suicide is actually a significant public health issue. The present work studies the mortality rates by suicide registered in Asturias between the years 1975 and 1994, being based on the data published by National Statistics Institute. The average annual suicide rate of the period was of 10.75 per 100,000 inhabitants, with a proportion man/woman of 2.3/1. The suicide rate increases with the age, so that the suicides of people older than 70 years meant 27% of the total of suicides in man and 36% of the total in women. A gradual increase of the phenomenon was evidenced in the temporary analysis, the standardized average annual rate went from 7.51 in 1974 to 12.91 in 1994. The annual rates increased in all the groups of age, but especially in young men and women in the decade of 40. The most used method of suicide was hanging, followed by throwing and immersion. It was evidenced a temporary trend to the increase of suicides by poisoning, shot by gun and throwing from a high place. The raise of suicide rates could be influenced by sociological factors, desinstitutionalization in mental health and accessibility to suicide methods. It is important to design prevention programs adapted to local characteristics.


Amino acids responsible for reduced affinities of vitamin K-dependent propeptides for the carboxylase.
The binding of the gamma-glutamyl carboxylase to its protein substrates is mediated by a conserved 18 amino acid propeptide sequence found in all vitamin K-dependent proteins. We recently found that the apparent affinities of the naturally occurring propeptides for the carboxylase vary over a 100-fold range and that the propeptide of bone Gla protein has severely impaired affinity for the carboxylase [Stanley, T. B., et al. (1999) J. Biol. Chem. 274, 16940-16944 (1)]. Here we report a consensus propeptide sequence that binds tighter (K(i) = 0.43 nM) to the carboxylase than any known propeptide sequence. Comparing the factor IX propeptide to the propeptides of protein C, bone Gla protein, and prothrombin, the weakest binding propeptides, allowed us to predict which residues might be responsible for these substrates' relatively weak binding to the carboxylase. We then made propeptides with the predicted amino acid changes and determined their binding affinities. The reduced binding affinity of these propeptides relative to that of FIX is due to residues -15 in protein C, -10 and -6 in bone Gla protein, and -9 in prothrombin. A role for the -9 position was not previously recognized but is further shown by our identification of a new, naturally occurring mutation at this position in factor IX which causes a warfarin-sensitive hemophilia B phenotype. In addition, we find that propeptides with mutations found in warfarin-sensitive patients have reduced affinity for the carboxylase, suggesting a physiological relevance of propeptide binding affinity.


Multicomponent Mannich reactions with boron enolates derived from diazo esters and 9-BBN.
Diazo esters, arylboranes, and carbamoyl imines undergo a 3-component Mannich condensation reaction. Catalyzed by Cu(II) salts, the reaction affords the corresponding isocyanate Mannich product: one that can be easily trapped in situ by other nucleophiles. The Mannich condensation corresponds to an α,α-disubstituted enolate addition to imines. The reaction was rendered asymmetric by using the (-)-phenylmenthol ester in good yield and selectivities.


Gene-directed enzyme prodrug therapy for osteosarcoma: sensitization to CPT-11 in vitro and in vivo by adenoviral delivery of a gene encoding secreted carboxylesterase-2.
Despite improvement in the treatment of osteosarcoma (OS), there are still many patients who cannot benefit from current treatment modalities. This warrants exploration of new treatment options. To that end, we investigated gene-directed enzyme prodrug therapy (GDEPT) with the use of human liver carboxylesterase-2 (CE2) and the anticancer agent CPT-11. CPT-11 is a clinically approved prodrug that needs to be metabolized into the active drug SN-38 by CEs, which occurs rather inefficiently in humans. GDEPT aims at high production of CE2 at the tumor site, resulting in efficient local conversion of CPT-11 into SN-38. Here, we show that OS cells transduced with an adenoviral vector containing the cDNA encoding a secreted form of CE2 (Ad-sCE2) expressed and efficiently secreted CE2. In vitro, transduction of a panel of OS cell lines with Ad-sCE2 resulted in sensitization up to 2800-fold to CPT-11 treatment. Primary OS short-term cultures, derived from patients suffering from a classic high-grade OS, demonstrated increased CPT-11 sensitivity up to 70-fold after transduction with Ad-sCE2 in vitro. When mice bearing s.c. MG-63 OS xenografts were intratumorally injected with Ad-sCE2 and CPT-11, this resulted in a significant difference in time to reach 2000 mm(3) in tumor volume as compared with animals receiving Ad-sCE2 or CPT-11 treatment (P < 0.05). Taken together, these data suggest that OS cells are sensitive for the combination of Ad-sCE2 and CPT-11.


The organochlorine pesticides pentachlorophenol and dichlorodiphenyltrichloroethane increase secretion and production of interleukin 6 by human immune cells.
The environmental contaminants pentachlorophenol (PCP) and 4, 4'-dichlorodiphenyltrichloroethane (DDT) are detected in some human blood samples at levels as high as 5 μM (PCP) and 260 nM (DDT). Several cancers are associated with exposures to these contaminants. IL-6 is a pro-inflammatory cytokine that when dysregulated stimulates inflammatory diseases and tumor progression. Immune cells exposed to PCP at 0.05-5 μM and DDT at 0.025-2.5 μM showed increased secretion of IL-6 when the cell preparations contained either T lymphocytes or monocytes. Increased IL-6 secretion was due to PCP and DDT induced cellular production of the cytokine and was dependent on MAP kinase signaling pathways (in the case of PCP). Compound-induced increases in IL-6 production were in part due to increases in either the transcription of and/or stability of its mRNA. Thus, both PCP and DDT have the potential to produce chronic inflammation by stimulating production of IL-6 by immune cells.


[Endovascular treatment of acute ischaemic stroke by means of a removable stent].
In this article, we describe the use of a novel mechanical thrombectomy device aimed at removing a thrombus in patients with acute ischaemic stroke and proximal intracranial arterial occlusion. A self-expandable stent is deployed into the thrombus which results in the immediate restoration of blood flow. After a few minutes, the thrombus will anchor itself onto the mesh of the stent. The stent and the captured thrombus are subsequently retrieved during aspiration of the guiding catheter.


Kcnq1ot1/Lit1 noncoding RNA mediates transcriptional silencing by targeting to the perinucleolar region.
The Kcnq1ot1 antisense noncoding RNA has been implicated in long-range bidirectional silencing, but the underlying mechanisms remain enigmatic. Here we characterize a domain at the 5' end of the Kcnq1ot1 RNA that carries out transcriptional silencing of linked genes using an episomal vector system. The bidirectional silencing property of Kcnq1ot1 maps to a highly conserved repeat motif within the silencing domain, which directs transcriptional silencing by interaction with chromatin, resulting in histone H3 lysine 9 trimethylation. Intriguingly, the silencing domain is also required to target the episomal vector to the perinucleolar compartment during mid-S phase. Collectively, our data unfold a novel mechanism by which an antisense RNA mediates transcriptional gene silencing of chromosomal domains by targeting them to distinct nuclear compartments known to be rich in heterochromatic machinery.


The incidence of postoperative hyponatremia and associated neurological sequelae in children with intracranial neoplasms.
Intracranial tumors are common pediatric neoplasms and account for substantial morbidity among children with cancer. Hyponatremia is a known complication of neurosurgical procedures and is associated with higher morbidity among neurosurgical patients. The authors aimed to estimate the incidence of hyponatremia, identify clinical characteristics associated with hyponatremia, and assess the association between hyponatremia and patient outcome among children undergoing surgery for intracranial tumors. This is a retrospective cohort study of children ranging in age from 0 to 19 years who underwent an initial neurosurgical procedure for an intracranial tumor between January 2001 and February 2012. Hyponatremia was defined as serum sodium ≤ 130 mEq/L during admission. Hyponatremia during admission occurred in 39 (12%) of 319 patients and was associated with young age and obstructive hydrocephalus (relative risk [RR] 2.9 [95% CI 1.3-6.3]). Hyponatremic patients were frequently symptomatic; 21% had seizures and 41% had altered mental status. Hyponatremia was associated with complicated care including mechanical ventilation (RR 4.4 [95% CI 2.5-7.9]), physical therapy (RR 4 [95% CI 1.8-8.8]), supplemental nutrition (RR 5.7 [95% CI 3.3-9.8]), and infection (RR 5.7 [95% CI 3.3-9.5]). Hyponatremic patients had a 5-fold increased risk of moderate or severe disability on the basis of their Pediatric Cerebral Performance Category score at discharge (RR 5.3 [95% CI 2.9-9.8]). Obstructive hydrocephalus (adjusted odds ratio [aOR] 3.24 [95% CI 1.38-8.94]) and young age (aOR 0.92 [95% CI 0.85-0.99]) were independently associated with hyponatremia during admission. Hyponatremia was independently associated with moderate or worse disability by Pediatric Cerebral Performance Category score at discharge (aOR 6.2 [95% CI 3.0-13.03]). Hyponatremia was common, particularly among younger children and those with hydrocephalus. Hyponatremia was frequently symptomatic and was associated with more complicated hospital courses. Hyponatremia was independently associated with worse neurological outcome when adjusted for age and tumor factors. This study serves as an exploratory analysis identifying important risk factors for hyponatremia and associated sequelae. Further research into the causes of hyponatremia and the association with poor outcome is needed to determine if prevention and treatment of hyponatremia can improve outcomes in these children.


Isometric force production parameters during normal and experimental low back pain conditions.
The control of force and its between-trial variability are often taken as critical determinants of motor performance. Subjects performed isometric trunk flexion and extension forces without and with experiment pain to examine if pain yields changes in the control of trunk forces. The objective of this study is to determine if experimental low back pain modifies trunk isometric force production. Ten control subjects participated in this study. They were required to exert 50 and 75% of their isometric maximal trunk flexion and extension torque. In a learning phase preceding the non painful and painful trials, visual and verbal feedbacks were provided. Then, subjects were asked to perform 10 trials without any feedback. Time to peak torque, time to peak torque variability, peak torque variability as well as constant and absolute error in peak torque were calculated. Time to peak and peak dF/dt were computed to determine if the first peak of dF/dt could predict the peak torque achieved. Absolute and constant errors were higher in the presence of a painful electrical stimulation. Furthermore, peak torque variability for the higher level of force was increased with in the presence of experimental pain. The linear regressions between peak dF/dt, time to peak dF/dt and peak torque were similar for both conditions. Experimental low back pain yielded increased absolute and constant errors as well as a greater peak torque variability for the higher levels of force. The control strategy, however, remained the same between the non painful and painful condition. Cutaneous pain affects some isometric force production parameters but modifications of motor control strategies are not implemented spontaneously. It is hypothesized that adaptation of motor strategies to low back pain is implemented gradually over time. This would enable LBP patients to perform their daily tasks with presumably less pain and more accuracy.


Electron-microscopic demonstration of multidrug resistance protein 2 (Mrp2) retrieval from the canalicular membrane in response to hyperosmolarity and lipopolysaccharide.
Immunohistochemical studies suggest that canalicular secretion via multidrug resistance protein 2 (Mrp2), a conjugate export pump encoded by the Mrp2 gene, is regulated by rapid transporter retrieval from/insertion into the canalicular membrane. The present study was undertaken in order to investigate this suggestion by means of immunogold electron microscopy. Therefore the effects of lipopolysaccharide (LPS) and osmolarity on Mrp2 localization were studied following immunogold labelling in the perfused rat liver by quantitative electron microscopy and morphometric analyses, and by confocal laser scanning microscopy. Mrp2 activity was assessed in the isolated perfused rat liver by measuring the excretion of dinitrophenyl-S-glutathione as a substrate of Mrp2. Both LPS and hyperosmolarity resulted in a statistically significant decrease in immunogold-labelled Mrp2 in the canalicular membrane and canalicular villi, and an increase in labelling in the pericanalicular cytoplasm. Canalicular morphometric parameters were unchanged under these conditions compared with controls. Under hyperosmolar perfusion Mrp2, but not the canalicular protein dipeptidylpeptidase IV, was found inside the cells, as shown by double immunofluorescence and confocal laser scanning microscopy. The findings suggest a selective retrieval of Mrp2 from the canalicular membrane under the influence of hyperosmolarity and LPS, whereas canalicular morphology remains unchanged.


Development and Application of "Cervical Dilatation Model for Teaching and Training".
Each year nursing schools pay more for teaching equipment at the nursing laboratory to improve practical skills. The development of the cervical dilatation model for teaching to reduce teaching and training costs is essential. This research aimed at developing a kind of cervical dilatation model for teaching and training. Developing a cervical dilatation model for teaching and training with the same structure and operation configuration is like the cervical dilatation model in laboratory practices of nursing. The appearance, structure, and operating accessories were developed from the original. The differences between the original cervical dilatation model and the cervical dilatation model for teaching and training are as follows: the original cervical dilatation model has only vaginal and fetal skulls of various sizes but the cervical dilatation model for teaching and training content follows vaginal, ischial spine, fetal skulls of various sizes, and cervical dilation and effacement. We then compare the teaching effect of the cervical dilatation model for teaching and training with the original cervical dilatation model (including knowledge, vaginal exam scores, and satisfaction after training). There was no significant difference in the knowledge and vaginal examination scores of the experimental group and control group before training. The vaginal examination scores in the experimental group were higher than those in the control group and scored before, immediately after, and two weeks after the intervention was statistically significantly higher than before training at 0.05 (68.86 ± 3.89, 88.10 ± 2.52, 91.06 ± 1.33) and the trainees had maximum satisfaction in the training. The cervical dilatation model for teaching and training was highly efficient, and knowledge and practice among nursing students in the intervention group increased after training. The cervical dilatation model for teaching and training could help reduce the cost of teaching equipment, increase teaching and training resources, and improve the trainee's knowledge and practice skills.


Assessment of metabolic responses following silica nanoparticles in zebrafish models using 1H NMR analysis.
Silica nanoparticles (SNPs) are widely explored as drug carriers, gene delivery vehicles, and as nanoparticles intended for bone and tissue engineering. SNPs are highly evident through various clinical trials for a wide range of biomedical applications. SNPs are biocompatible and promising nanoparticles for next-generation therapeutics. However, despite the well-established importance of SNPs, metabolomics methods for the SNPs remain elusive which renders its maximal clinical translation. We applied 1H nuclear magnetic resonance (1H NMR) spectroscopy to investigate the metabolomics profile in Zebrafish (Danio rerio) exposed to SNPs. Zebrafish were exposed to the SNPs (10.0, 25.0, and 50.0 μg/mL) for 72 h and whole-body samples were subjected for targeted profiling. Pattern recognition of 1H NMR spectral data depicted alterations in the metabolomic profiles between control and SNPs exposed zebrafish. We found that tryptophane, lysine, methionine, phenylalanine, tyrosine, sn-glycero-3-phosphocholine (G3PC), and o-phosphocholine were decreased. The metabolic expression of niacinamide, nicotinamide adenine dinucleotide (NAD+), citrate, adenosine triphosphate (ATP), and xanthine were increased in zebrafish with SNPs treatment. We are report for the first time on metabolite alterations and phenotypic expression in zebrafish via 1H NMR. These results demonstrate that SNPs can adversely affect the significant metabolic pathways involved in energy, amino acids, cellular membrane, lipids, and fatty acid metabolisms. Metabolomics profiling may be able to detect metabolic dysregulation in SNPs-treated zebrafish and establish a foundation for further toxicological studies.


Preadipocyte number in omental and subcutaneous adipose tissue of obese individuals.
To determine the variation in preadipocyte isolation procedure and to assess the number and function of preadipocytes from subcutaneous and omental adipose tissue of obese individuals. The preadipocyte number per gram of adipose tissue in the abdominal-subcutaneous and abdominal-omental adipose stores of 27 obese subjects with a BMI of 44 +/- 10 kg/m(2) and an age of 40 +/- 9 years was determined. The assessment of the preadipocyte number was found to be labor intensive and error prone. Our data indicated that the number of stromal vascular cells (SVCs), isolated from the adipose tissue by collagenase digestion, was dependent on the duration of collagenase treatment and the size and the origin of the biopsy. In addition, the fat accumulation and leptin production by differentiated SVCs were dependent on the number of adherent SVCs (aSVCs) in the culture plate and the presence of proteins derived from serum and peroxisome proliferator-activated receptor ligands. Using our standardized isolation and differentiation protocol, we found that the number of SVCs, aSVCs, leptin production, and fat accumulation still varied considerably among individuals. Interestingly, within individuals, the number of SVCs, aSVCs, and the leptin production by differentiating aSVCs from both the subcutaneous and the omental fat depots were associated, whereas fat accumulation was not. In obese to severely obese subjects, differences in BMI and age could not explain differences in SVCs, aSVCs, leptin production, and fat accumulation.


Laser beam directed at the lunar retro-reflector array: observations of the first returns.
On 1 August between 10:15 and 12:50 Universal Time, with the Lick Observatory 120-inch (304-cm) telescope and a laser operating at 6943 angstroms, return signals from an optical retro-reflector array placed on the moon by the Apollo 11 astronauts were successfully detected. After the return signal was first detected it continued to appear with the expected time delay for the remainder of the night. The observed range is in excellent agreement with the predicted ephemeris. Transmitting between 7 and 8 joules per pulse, we found that each return signal averaged more than one photoelectron. This is in good agreement with calculations of the expected signal strength.


The myelin-associated glycoproteins: membrane disposition, evidence of a novel disulfide linkage between immunoglobulin-like domains, and posttranslational palmitylation.
The myelin-associated glycoproteins (MAG) are members of the immunoglobulin gene superfamily that function in the cell interactions of myelinating glial cells with axons. In this paper, we have characterized the structural features of these proteins. The disposition of MAG in the bilayer as a type 1 integral membrane protein (with an extracellularly disposed amino terminus, single transmembrane segment, and cytoplasmic carboxy terminus) was demonstrated in protease protection studies of MAG cotranslationally inserted into microsomes in vitro and in immunofluorescent studies with site specific antibodies. A genetically engineered MAG cDNA, which lacks the putative membrane spanning segment, was constructed and shown to encode a secreted protein. These results confirm the identify of this hydrophobic sequence as the transmembrane segment. Sequencing of the secreted protein demonstrated the presence of a cleaved signal sequence and the site of signal peptidase cleavage. To characterize the disulfide linkage pattern of the ectodomain, we cleaved MAG with cyanogen bromide and used a panel of antibodies to coprecipitate specific fragments under nonreducing conditions. These studies provide support for a novel disulfide linkage between two of the immunoglobulin domains of the extracellular segment. Finally, we report that MAG is posttranslationally palmitylated via an intramembranous thioester linkage. Based on these studies, we propose a model for the conformation of MAG, including its RGD sequence, which is considered with regard to its function as a cell adhesion molecule.


Diversification dynamics of a common deep-sea octocoral family linked to the Paleocene-Eocene thermal maximum.
The deep-sea has experienced dramatic changes in physical and chemical variables in the geological past. However, little is known about how deep-sea species richness responded to such changes over time and space. Here, we studied the diversification dynamics of one of the most diverse octocorallian families inhabiting deep sea benthonic environments worldwide and sustaining highly diverse ecosystems, Primnoidae. A newly dated species-level phylogeny was constructed to infer their ancestral geographic locations and dispersal rates initially. Then, we tested whether their global and regional (the Southern Ocean) diversification dynamics were mediated by dispersal rate and abiotic factors as changes in ocean geochemistry. Finally, we tested whether primnoids showed changes in speciation and extinction at discrete time points. Our results suggested primnoids likely originated in the southwestern Pacific Ocean during the Lower Cretaceous ∼112 Ma, with further dispersal after the physical separation of continental landmasses along the late Mesozoic and Cenozoic. Only the speciation rate of the Southern Ocean primnoids showed a significant correlation to ocean chemistry. Moreover, the Paleocene-Eocene thermal maximum marked a significant increase in the diversification of primnoids at global and regional scales. Our results provide new perspectives on the macroevolutionary and biogeographic patterns of an ecologically important benthic organism typically found in deep-sea environments.


[Incorporation of Na,K-ATPase into human erythrocyte membranes using liposomes].
A procedure for incorporation of isolated cattle brain Na,K-ATPase into erythrocyte membranes by proteoliposomes has been elaborated. The Na,K-ATPase activity of proteoliposome-treated human erythrocytes containing incorporated Na,K-ATPase does not exceed that of control erythrocytes. In the erythrocyte membrane the incorporated enzyme exists in a functionally active state and retains the vector properties of the Na+-pump. Exogenous ATP stimulates 22Na influx and 86Rb efflux in and from the erythrocytes.


Cytokine Release Syndrome During Sequential Treatment With Immune Checkpoint Inhibitors and Kinase Inhibitors for Metastatic Melanoma.
Switching from immunotherapy to targeted therapy in metastasized melanoma can be complicated by a cytokine release syndrome (CRS). CRS is a serious complication, which is induced by high levels of circulating cytokines, associated with T-cell engagement and proliferation, and results in a constellation of symptoms with variable organ involvement. We report 2 patients with BRAF V600 mutant melanoma who were previously treated with anti-PD-1±anti-LAG-3 antibodies and were switched to BRAF/MEK-inhibitors because of progressive disease. Both cases depict the complexity of interactions occurring during sequential treatment with immune checkpoint inhibitors and kinase inhibitors. Early identification and management of CRS is crucial to decrease its toxicity and improve safety of further drugs to be given in a therapeutic ladder.


Evaluation of Aflatoxin M1 enrichment factor in different cow milk cheese hardness category.
Aflatoxin M1 (AFM1) is a hepatocarcinogenic and genotoxic derivative of aflatoxin B1 excreted into milk after ingestion of feed contaminated by Aspergillus genus fungi. Because of the important role of dairy products, especially cow cheese, in the human diet, there is great concern about the presence of AFM1 in this food category. EC Regulation No. 1881/2006 establishes the importance of the enrichment factor (EF), an essential parameter that must be defined in order to evaluate the maximum level of the toxin in cheese aiming to ensure that cheese has been produced from compliant milk. The Italian Ministry of Health has established two provisional AFM1 EFs (5.5 and 3.0) to be applied to as many cheese categories (hard and soft), defined according to the moisture content on a fat free basis (MFFB) classification. Two experimental productions of Primosale and Fior di Latte cheese, both belonging to the soft cheese category, showed an EF of 4.1 and 2.9 respectively. Data in literature also suggest that the EF attribution based on the current categorization may need reconsideration.


Common resting brain dynamics indicate a possible mechanism underlying zolpidem response in severe brain injury.
Zolpidem produces paradoxical recovery of speech, cognitive and motor functions in select subjects with severe brain injury but underlying mechanisms remain unknown. In three diverse patients with known zolpidem responses we identify a distinctive pattern of EEG dynamics that suggests a mechanistic model. In the absence of zolpidem, all subjects show a strong low frequency oscillatory peak ∼6-10 Hz in the EEG power spectrum most prominent over frontocentral regions and with high coherence (∼0.7-0.8) within and between hemispheres. Zolpidem administration sharply reduces EEG power and coherence at these low frequencies. The ∼6-10 Hz activity is proposed to arise from intrinsic membrane properties of pyramidal neurons that are passively entrained across the cortex by locally-generated spontaneous activity. Activation by zolpidem is proposed to arise from a combination of initial direct drug effects on cortical, striatal, and thalamic populations and further activation of underactive brain regions induced by restoration of cognitively-mediated behaviors. DOI: http://dx.doi.org/10.7554/eLife.01157.001.


The SH integral membrane protein of the paramyxovirus simian virus 5 is required to block apoptosis in MDBK cells.
In some cell types the paramyxovirus simian virus 5 (SV5) causes little cytopathic effect (CPE) and infection continues productively for long periods of time; e.g., SV5 can be produced from MDBK cells for up to 40 days with little CPE. SV5 differs from most paramyxoviruses in that it encodes a small (44-amino-acid) hydrophobic integral membrane protein (SH). When MDBK cells were infected with a recombinant SV5 containing a deletion of the SH gene (rSV5DeltaSH), the MDBK cells exhibited an increase in CPE compared to cells infected with wild-type SV5 (recovered from cDNA; rSV5). The increased CPE correlated with an increase in apoptosis in rSV5DeltaSH-infected cells over mock-infected and rSV5-infected cells when assayed for annexin V binding, DNA content (propidium iodide staining), and DNA fragmentation (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay). In rSV5DeltaSH-infected MDBK cells an increase in caspase-2 and caspase-3 activities was observed. By using peptide inhibitors of individual caspases it was found that caspase-2 and caspase-3 were activated separately in rSV5DeltaSH-infected cells. Expression of caspase-2 and -3 in rSV5DeltaSH-infected MDBK cells appeared not to require STAT1 protein, as STAT1 protein could not be detected in SV5-infected MDBK cells. When mutant mice homologous for a targeted disruption of STAT1 were used as a model animal system and infected with the viruses it was found that rSV5DeltaSH caused less mortality than wild-type rSV5, consistent with the notion of clearance of apoptotic cells in a host species.


Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas.
Primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the latest 2016 World Health Organization Classification of Cutaneous lymphomas. We sought to better characterize and provide diagnostic and therapeutic guidance of this rare cutaneous lymphoma. Thirty-four patients with a median age of 77 years (range 19-89 years) presented primarily with extensive annular necrotic plaques or tumor lesions with frequent mucous membrane involvement. The 5-year survival was 32% with a median survival of 12 months. A subset of 17 patients had a prodrome of chronic patches prior to the development of aggressive ulcerative lesions. We identified cases with lack of CD8 or αβ T-cell receptor expression yet with similar clinical and pathological presentation. Allogeneic stem cell transplantation provided partial or complete remissions in 5/6 patients. We recommend the term primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma as this more broad designation better describes this clinical-pathologic presentation, which allows the inclusion of cases with CD8 negative and/or αβ/γδ T-cell receptor chain double-positive or double-negative expression. We have identified early skin signs of chronic patch/plaque lesions that are often misdiagnosed as eczema, psoriasis, or mycosis fungoides. Our experience confirms the poor prognosis of this entity and highlights the inefficacy of our standard therapies with the exception of allogeneic stem cell transplantation in selected cases.


Metabolism and difference iterative forecasting model based on long-range dependent and grey for gearbox reliability.
The reliability prediction of gearbox is a complex and challenging topic. The purpose of this research is to propose a hybrid difference iterative forecasting model to forecast reliability of the gearbox. On this score, a hybrid model based on the fractional Lévy stable motion (fLsm), the Grey Model (GM) and the metabolism method is proposed. To solve the problem of insensitivity to weak faults inside the gearbox, we use feature extraction method to reveal the gearbox degradation. Then, the least square theory is used to separate the degradation sequence in the gearbox into a deterministic term with monotonicity and a stochastic term with Long-Range Dependence (LRD). Next, the fLsm with LRD and non-Gaussian is used to forecast the stochastic term, the deterministic term is simulated by the GM, and the hybrid forecasting model is used to modify the prediction results. The metabolism method is used to update the degradation sequence and to forecast longer-term trend. Finally, a case demonstrated that superiority and generality of the hybrid forecasting model.


Gene Flow Between Bt and Non-Bt Plants in a Seed Mixture Increases Dominance of Resistance to Pyramided Bt Corn in Helicoverpa zea (Lepidoptera: Noctuidae).
For delaying evolution of pest resistance to transgenic corn producing Bacillus thuringiensis (Bt) toxins, limited data are available to compare the effectiveness of refuges of non-Bt corn planted in seed mixtures versus blocks. Here we addressed this issue in the ear-feeding pest Helicoverpa zea Boddie by measuring its survival and development in the laboratory on ears from field plots with 90% Cry1A.105 + Cry2Ab corn and 10% non-Bt corn planted in a seed mixture or blocks. We compared a strain of H. zea selected for resistance to Cry1Ac in the laboratory, its parent strain not selected in the laboratory, and their F1 progeny. The relative survival of the F1 progeny and dominance of resistance were higher on ears from Bt plants in the seed mixture than the block. Half of the kernels in ears from non-Bt plants in the seed mixture produced both Cry1A.105 and Cry2Ab. However, survival on ears from non-Bt plants did not differ between the block and seed mixture. In simulations based on the observed survival, resistance to Cry1A.105 + Cry2Ab corn evolved faster with the seed mixture than the blocks, because of the higher dominance of resistance in the seed mixture. Increasing the refuge percentage improved durability of Cry1A.105 + Cry2Ab corn more for the blocks than the seed mixture. These findings imply that, for a given percentage of non-Bt corn, resistance of H. zea and other ear-feeding pests to multi-toxin Bt corn is likely to evolve faster for seed mixtures than blocks.


A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction.
Members of the transforming growth factor-beta superfamily play critical roles in controlling cell growth and differentiation. Effects of TGF-beta family ligands are mediated by Smad proteins. To understand the mechanism of Smad function, we sought to identify novel interactors of Smads by use of a yeast two-hybrid system. A 396-amino acid nuclear protein termed SNIP1 was cloned and shown to harbor a nuclear localization signal (NLS) and a Forkhead-associated (FHA) domain. The carboxyl terminus of SNIP1 interacts with Smad1 and Smad2 in yeast two-hybrid as well as in mammalian overexpression systems. However, the amino terminus of SNIP1 harbors binding sites for both Smad4 and the coactivator CBP/p300. Interaction between endogenous levels of SNIP1 and Smad4 or CBP/p300 is detected in NMuMg cells as well as in vitro. Overexpression of full-length SNIP1 or its amino terminus is sufficient to inhibit multiple gene responses to TGF-beta and CBP/p300, as well as the formation of a Smad4/p300 complex. Studies in Xenopus laevis further suggest that SNIP1 plays a role in regulating dorsomedial mesoderm formation by the TGF-beta family member nodal. Thus, SNIP1 is a nuclear inhibitor of CBP/p300 and its level of expression in specific cell types has important physiological consequences by setting a threshold for TGF-beta-induced transcriptional activation involving CBP/p300.


Effect of enalapril therapy on glomerular accumulation of immune complexes and mesangial matrix in experimental glomerulonephritis in the nonhuman primate.
The present study is a prospective, controlled, blinded trial of enalapril therapy in experimental immune complex (IC)-mediated glomerulonephritis (GN) in the nonhuman primate (cynomolgus monkey [CYN]). Two groups of CYNs were studied: those with established GN (study A) and those in which GN was being induced (study B). In study A, 12 CYNs had GN established by 8 or 10 weeks of daily intravenous infusion of bovine gamma-globulin (BGG). These CYNs were then assigned to either 4 weeks of daily oral enalapril therapy (n = 6) or daily oral placebo therapy (n = 6). The daily BGG infusions were continued during the 4 weeks of enalapril or placebo therapy. At the start of the enalapril/placebo protocol, the two groups were similar with respect to proteinuria and level of precipitating antibody to BGG, which determined the daily BGG dose. Renal biopsy was performed in each CYN at the start and end of the 4-week period of enalapril/placebo protocol. In study B, 15 normal CYNs were immunized to BGG over a period of 4 weeks. The CYNs were then assigned to daily oral enalapril therapy (n = 8) or placebo therapy (n = 7) based on level of precipitating antibody to BGG. At this point, daily intravenous BGG was begun along with daily enalapril or placebo for 8 weeks. Renal biopsy was performed in each CYN before and at the end of this 8-week period. In study A, enalapril therapy was associated with a significant decrease in mesangial matrix volume (mean change, -27.7%; P = 0.031) and a trend toward decreased mesangial matrix deposits (mean change, -34.1%; P = 0.188). By contrast, in CYNs receiving placebo therapy, mesangial matrix volume increased compared with the enalapril group (P = 0.002) and mesangial deposits were unchanged. In study B, both the enalapril and placebo groups showed significant increases in mesangial matrix volume, mesangial deposits, mesangial cell volume, and capillary wall deposits during the 8 weeks of daily BGG infusion. However, none of the differences between the groups achieved statistical significance. Changes in mesangial cell volume and capillary wall deposits were also evaluated in study A and study B, but were not found to be different between the enalapril and placebo groups. In both study A and study B, blood pressure was lower in the enalapril groups. In conclusion, in the initial phase of IC-GN induction (0 to 8 weeks), enalapril therapy does not significantly influence the glomerular accumulation of mesangial matrix or immune deposits. However, in established IC-GN (after 8 weeks of GN induction), enalapril therapy significantly decreases the further accumulation of mesangial matrix and may decrease the further accumulation of mesangial deposits. Whether this benefit of enalapril therapy was related to lower blood pressure or to other effects of angiotensin-converting enzyme (ACE) inhibition was not determined in this study.


Long non-coding RNA HOTAIR promotes cell viability, migration and invasion in thyroid cancer cells by sponging miR-17-5p.
Thyroid cancer is a common endocrine malignancy. Long non-coding RNAs (lncRNAs) were reported to regulate cellular processes in tumorigenesis and development. In this study, we mainly investigated the role of Homeobox Transcript Antisense Intergenic RNA (HOTAIR) in thyroid cancer and its potential mechanism. RT-qPCR was conducted to evaluate the expression of HOTAIR and miR-17-5p in thyroid cancer tissues and 4 cell lines (TPC-1, FTC-133, B-CPAP and SW579). MTT assay was employed to analyze the cell viability of TPC-1 and FTC-133 cells. The migration and invasion of TPC-1 and FTC-133 cells were detected via Transwell assay. Luciferase reporter assay was used to validate the target of HOTAIR. In vivo tumor formation assay in nude mice was applied to investigate the impact of HOTAIR on thyroid cancer tumorigenesis. HOTAIR was significantly upregulated, while miR-17-5p was downregulated in thyroid cancer tissues and cells, and the miR-17-5p expression in thyroid cancer tissues was inversely correlated with HOTAIR expression. Silencing HOTAIR significantly inhibited the cell viability, migration and invasion of TPC-1 and FTC-133 cells. MiR-17-5p was a target of HOTAIR and counter-regulated by HOTAIR. Introduction of miR-17-5p also inhibited the cell viability, migration and invasion in TPC-1 and FTC-133 cells. Moreover, introduction of miR-17-5p reversed knockdown of HOTAIR-mediated the suppression effects on the cell viability, migration and invasion in thyroid cancer cells. Additionally, knockdown of HOTAIR inhibited thyroid cancer tumorigenesis in mice. Our results suggested HOTAIR promotes cell viability, migration and invasion in thyroid cancer cells by sponging miR-17-5p.


Measuring the significance of field validation in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology: how good are the experts?
Expert opinion is often used as a gold standard for gynecologic cytology in the evaluation of new technologies, in the legal setting, and in the validation of cases for use in educational programs and proficiency testing. However, the reliability of expert opinion alone in selecting slides of a specific cytodiagnosis that can be reproducibly and reliably identified by subsequent reviewers has not been determined. To assess the ability of expert opinion to select slides that are validated in subsequent reviews. In the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology, each case in every cytodiagnostic category is accepted for circulation only after review by 3 expert cytopathologists. The percentage of these cases that could not be reliably and reproducibly identified by program participants for each cytodiagnostic category ("failed field validation") was determined during the duration of the program from 1989 to 2004. More than 10,000 conventional smears and ThinPrep cases were selected by the expert panel for circulation. Of these selected slides, 19% of conventional smears and 15% of ThinPrep specimens failed field validation. Compared with the overall slide performance, significantly higher percentages (P < .001) of conventional smears with reference diagnoses of unsatisfactory (51.7%), repair (58%), or low-grade intraepithelial lesion (31.8%) and of ThinPrep specimens with reference diagnoses of unsatisfactory (54.5%) and repair (76.9%) failed field validation. In contrast, significantly lower percentages of conventional smears with reference diagnoses of squamous cell carcinoma (4.5%), high-grade squamous intraepithelial lesion (9%), Trichomonas vaginalis infection (11.7%), or herpes (9.9%) and of ThinPrep specimens with reference diagnoses of adenocarcinoma (5.1%), herpes (2.1%), and fungal organism consistent with Candida (8.4%) failed field validation (P < .001 for all). Between 15% and 19% of gynecologic cytologic cases that have been selected by expert cytopathologists as good examples of cytodiagnostic abnormalities fail field validation. The proportion of cases failing field validation varies with cytodiagnostic category, but it occurs in all cytodiagnostic entities.


Ser-3 is important for regulating Mos interaction with and stimulation of mitogen-activated protein kinase kinase.
Mos is a germ cell-specific serine/threonine protein kinase that activates mitogen-activated protein kinase (MAPK) through MAPK kinase (MKK). In Xenopus oocytes, Mos synthesis is required for progesterone-induced activation of MAPK and maturation promoting factor. Injection of Mos or active MAPK causes mitotic arrest in early embryos, suggesting that Mos also acts via MKK and MAPK to induce the arrest of unfertilized eggs in metaphase of meiosis II. We have investigated whether Mos activity is regulated by phosphorylation. Previous studies have identified Ser-3 as the principal autophosphorylation site. We show that Mos interacts with the catalytic domain of MKK in a Saccharomyces cerevisiae two-hybrid test. Acidic substitutions of the sites phosphorylated by Mos in MKK reduce the interaction, implying that the complex may dissociate after phosphorylation of MKK by Mos. Furthermore, the Mos-MKK interaction requires Mos kinase activity, suggesting that Mos autophosphorylation may be involved in the interaction. Substitution of Ser-3 of Mos with Ala reduces the interaction with MKK and also reduces both the activation of MKK by Mos in vitro and cleavage arrest induced by Mos fusion protein in Xenopus embryos. By contrast, substitution of Ser-3 by Glu, an acidic amino acid that mimics phosphoserine, fosters the Mos interaction with MKK and permits activation of MKK in vitro and Mos-induced cleavage arrest. Moreover, the Glu-3 substitution increases the interaction of a kinase-inactive Mos mutant with MKK. Taken together, these results suggest that an important step in Mos activation involves the phosphorylation at Ser-3, which promotes Mos interaction with and activation of MKK.


[The Hypertrophy of Autonomy in the Bioethical Debate].
In the current bioethical debate personal autonomy is frequently used as an argument to justify the legalization of new options for the subject. This is the case, for instance, of the controversies around surrogated motherhood, organ free market, euthanasia or egg freezing in order to postpone motherhood. This paper aims to show how legalizing certain options can be harmful to people, and would justify and perpetuate situations of domination of some human beings over others. In this regard, the importance of recognizing the unavailability of certain goods and human rights is underlined.


A gold nanoshell with a silica inner shell synthesized using liposome templates for doxorubicin loading and near-infrared photothermal therapy.
Gold (Au) nanoshells with solid silica cores have great potential for cancer photothermal therapy. However, this nanostructure cannot carry enough drugs. Here, we report a Au nanoshell with a hollow silica core for drug loading and cancer therapy. The silica shells were synthesized using nanoliposome templates, and then Au nanoshells were grown on the outer surface of the silica shells. Transmission-electron and scanning-electron microscopy showed that the Au nanoshells were successfully fabricated, and that the liposome/SiO(2)/Au core-shell nanocomposites were spherical with a narrow size distribution. Images of several broken spheres, and the fact that hollow templates (liposomes) were used, suggest that the fabricated Au nanoshells were hollow. After doxorubicin (DOX) was incorporated into liposome/SiO(2)/Au, the DOX-loaded Au nanoshells killed cancer cells with high therapeutic efficacy when irradiated with near-infrared light, suggesting that the Au nanoshells delivered both DOX chemotherapy and photothermal therapy with a synergistic effect.


Circulation of imipenem-resistant Acinetobacter baumannii ST10, ST2 and ST3 in a university teaching hospital from Tehran, Iran.
Multi-drug resistant (MDR) Acinetobacter baumannii has introduced a worldwide health crisis. The purposes of this study were to characterize the clonal relatedness among MDR clinical strains and to introduce a new two-locus typing method confirmed by multi-locus sequence typing (MLST). In this study, we determined antimicrobial resistance, detected genes associated with carbapenem resistance and characterized clonal relatedness among 99 clinical isolates extracted from 82 hospitalized inpatients in a university hospital. Of the 99 A. baumannii isolates, 92.9% (92/99) were resistant to imipenem and 97.9% (97/99) had an MDR profile. We found that the high prevalence of blaVIM [94.9% (94/99)] and blaOXA-23-like [93.93% (93/99)] is the main mechanism of carbapenem resistance. This study proposes a new two-locus typing (blaOXA-51-like and ampC) method for the rapid identification of clonal complexes (CCs). The results of this method and confirmation by MLST show that clinical isolates carry blaOXA-68 as well as ampC-10 or ampC-20 genes belonging to CC10 (ST10); blaOXA-66 and ampC-2 belonging to CC2 (ST2); and blaOXA-71 and ampC-3 belonging to CC3 (ST3). One isolate had blaOXA-90 with an undetermined allele number of ampC belonging to ST513. The high prevalence of MDR strains and the circulation of four limited clones, including ST10 (45/99), ST2 (41/99), ST3 (12/99) and ST513 (1/99), in the clinical setting highlights the importance of a rigorous infection control programme. The two-locus typing method has more discrimination than the application of each method separately and it could be applied for the rapid determination of the CC without performing MLST.


Extensive cardiopulmonary resuscitation of preterm neonates at birth and mortality and developmental outcomes.
To compare mortality and neurodevelopmental outcomes of extremely low gestational age neonates who received delivery room extensive cardiopulmonary resuscitation (DR-CPR) to those who did not require DR-CPR. Preterm neonates born at <29 weeks' gestational age between January 2010 and September 2011 and assessed at Canadian Neonatal Follow-Up Network centers were studied. Neonates who received DR-CPR were compared to those who did not require DR-CPR using univariate and multivariable analyses. The primary outcome was a composite of mortality or any neurodevelopmental impairment at 18 to 24 months corrected age defined as the presence of any one or more of the following: cerebral palsy; Bayley-III cognitive, language, or motor composite scores <85 on any one of the components; sensorineural/mixed hearing loss or unilateral or bilateral visual impairment. Secondary outcomes were the individual components of the composite outcomes. Of the 2760 neonates born, 173 were excluded and remaining 2587 eligible neonates were included in our study. Of these 2068 had outcome data (80%) of whom 190 (9.2%) received DR-CPR. DR-CPR was independently associated with mortality or neurodevelopmental impairment (adjusted odds ratio [aOR] 1.76; 95% CI 1.21-2.55) and mortality alone (aOR1.94; 95% CI 1.33-2.83). DR-CPR was also associated with increased odds of motor impairment (aOR 2.03; 95% CI 1.28-3.23). In extremely low gestational age neonates, DR-CPR was associated with higher odds of the composite outcome of mortality or neurodevelopmental impairment, mortality alone, and lower motor scores at 18 to 24 months' corrected age.