Induction of the endoplasmic reticulum stress and autophagy in human lung carcinoma A549 cells by anacardic acid.
Anacardic acid (AA, 2-hydroxy-6-pentadecylbenzoic acid), a constituent of the cashew-nut shell, has a variety of beneficial effects on the treatment of cancer and tumors. However, the fact that AA induces ER stress and autophagy in cancer cell is not known. We investigated the effect of AA on ER-stress and autophagy-induced cell death in cancer cells. Because of our interest in lung cancer, we used the non-small cell lung adenocarcinoma A549 cells treated with 3.0 μg/ml of AA for this research. In this research we found that AA induces intracellular Ca(2+) mobilization and ER stress. AA induced the ER stress-inducing factors, especially IRE1α, and the hallmarks of UPR, Grp78/Bip and GADD153/CHOP. AA inhibited the expression of p-PERK and its downstream substrate, p-elF2α. We also demonstrated that AA induces autophagy. Up-regulation of autophagy-related genes and the appearance of autophagosome in transfected cells with green fluorescent protein (GFP)-LC3 and GFP-Beclin1 plasmids showed the induction of autophagy in AA-treated A549 cells. The morphological analysis of intracellular organelles by TEM also showed the evidence that AA induces ER stress and autophagy. For the first time, our research showed that AA induces ER stress and autophagy in cancer cells.


Variations of thoracoabdominal volumes after lung transplantation measured by opto-electronic plethysmography.
Lung function after lung transplantation (LTx) has been widely studied. On the contrary, the thoracoabdominal volume rearrangement after LTx has yet to be investigated. Patients with cystic fibrosis and listed for double LTx at our institution were enrolled for the prospective study to explore the effects of LTx on the rearrangement of respiratory volumes in patients affected by cystic fibrosis, by utilizing the opto-electronic plethysmography (OEP), a noninvasive method to study the volume and motion of the human trunk. Rib cage and abdominal volumes were tested with OEP (OEP system, BTS, Milano, Italy). Eight patients were enrolled (male-to-female ratio: 1:3; mean age 29.3 ± 7.8 years). After LTx the volume changes analyzed with OEP revealed a significant decrease of the total lung capacity (TLC) as well as the functional residual capacity and residual volume when the chest wall volume was considered. Dividing the whole respiratory volume in the three compartments showed different trends. We consider OEP a particularly useful device in patients with severe respiratory disease, in that it allows a noninvasive estimate of the volume change of the chest wall. This study demonstrates a significant reduction of thoracoabdominal volumes in patients affected by cystic fibrosis treated with bilateral LTx. Abdomen and upper rib cage were congruent with the volume reduction, while the lower rib cage showed an opposite tendency.


Influence of the design of the prosthesis on the outcome after hemiarthroplasty of the shoulder in displaced fractures of the head of the humerus.
We reviewed 39 patients with displaced three- and four-part fractures of the humerus. In 21 patients (group A) we had used an anatomical prosthesis for the humeral head and in 18 (group B) an implant designed for fractures. When followed up at a mean of 29.3 months after surgery the overall Constant score was 51.9 points; in group A it was 51.5 and in group B 52.4 points. The subjective satisfaction of the patients was assessed using a numerical rating scale and was similar in both groups. In group A complete healing of the tuberosities was found in 29% and 50% in group B. Partial integration was seen in 29% of group A and in only one patient in group B, while resorption was noted in 43% of group A and 44% of group B. The functional outcome was significantly better in patients with complete or partial healing of the tuberosities (p=0.022). The specific trauma prosthesis did not lead to better healing of the tuberosities. The difference in clinical outcome obtained by the two designs did not reach statistical significance.


Human tuberculosis brain promotes neuronal apoptosis but not in astrocytes with high expression of vascular endothelial growth factor.
The present study aimed to investigate the involvement of the angiogenic marker vascular endothelia growth factor (VEGF) and apoptotic markers of Bcl-2 and Bax in the neurons and astrocytes in the brain infected by Mycobacterium tuberculosis. The immunohistochemistry staining was performed to analyze the expression of the VEGF, Bcl-2 and Bax in the astrocytes and neurons. The expression of VEGF was high in neurons and astrocytes in both the infected brain and control tissues with no difference of angiogenic activity (p = 0.40). Higher Bcl-2 expression was seen in astrocytes of infected brain tissues compared to the control tissues (p = 0.004) promoted a higher anti-apoptotic activity in astrocytes. The neurons expressed strong Bax expression in the infected brain tissues compared to the control tissues (p < 0.001), which indicated more apoptosis in neurons. Thus, neuronal death and survival of infected astrocytes together with high expression of VEGF might be associated with formation of brain tuberculosis. In conclusion, neurons could be more vulnerable than astrocytes in human tuberculosis brain with high expression of VEGF.


Ocular pain and discomfort after advanced surface ablation: an ignored complaint.
Laser vision correction is one of the most commonly performed elective surgical procedures in ophthalmology. Generally, discomfort besides pain (photophobia, burning sensation, tearing, and foreign body sensation) after these procedures is not taken into consideration in the clinical practice. The objective is to provide data on these symptoms and their relevance after advanced surface ablation (ASA). Single-center survey study based on a structured questionnaire relative to the patients' perceived symptoms after ASA. Inclusion criteria were: ≥18 years old, no ocular disease, with myopia (0.75 to 9 D) or hyperopia (0.25 to 5 D) with or without astigmatism, receiving ASA on at least one eye. All procedures were performed by the same surgeon. A descriptive analysis was performed. Seventy-three consecutive patients (34 men and 39 women) were included in the study. The median (range) of age was 33 (19-64) years. Sixty-nine patients had surgery done on both eyes. Postoperative pain was the most frequent comorbidity (97% [95% confidence interval {CI}: 90-100]) with a median (range) of intensity (verbal numerical rating scale) score of 7 (2-10). Photophobia: 85% (95% CI: 75-92); burning sensation: 62% (95% CI: 50-73); tearing: 59% (95% CI: 47-70); and foreign body sensation: 48% (95% CI: 36-60) were also prevalent postoperative symptoms. Pain during ASA was reported for 44% (95% CI: 32-56) of patients. Comorbidities such as pain, photophobia, burning sensation, tearing, and foreign body sensation are prevalent after ASA procedure. Postoperative pain should be taken into consideration due to its prevalence and intensity. A new and more efficient postoperative analgesic protocol should be established.


Prescribing patterns of antibiotics and sensitivity patterns of common microorganisms in the Internal Medicine ward of a teaching hospital in Western Nepal: a prospective study.
Information about antibiotic use and resistance patterns of common microorganisms are lacking in hospitals in Western Nepal. Excessive and inappropriate use of antibiotics contributes to the development of bacterial resistance. The parameter: Defined daily dose/100 bed-days, provides an estimate of consumption of drugs among hospital in-patients. This study was carried out to collect relevant demographic information, antibiotic prescribing patterns and the common organisms isolated including their antibiotic sensitivity patterns. The study was carried out over a 3-month period (01.04.2002 to 30.06.2002) at the Manipal Teaching Hospital, Western Nepal. The median number of days of hospitalization and mean +/- SD cost of antibiotics prescribed during hospital stay were calculated. The use of antibiotics was classified for prophylaxis, bacteriologically proven infection or non-bacteriologically proven infection. Sensitivity patterns of the common organisms were determined. Defined daily dose/100 bed-days of the ten most commonly prescribed antibiotics were calculated. 203 patients were prescribed antibiotics; 112 were male. Median duration of hospitalization was 5 days. 347 antibiotics were prescribed. The most common were ampicillin, amoxicillin, metronidazole, ciprofloxacin and benzylpenicillin. Mean +/- SD cost of antibiotics was 16.5 +/-13.4 US dollars. Culture and sensitivity testing was carried out in 141 patients. The common organisms isolated were H. influenzae, E. coli, K. pneumoniae and S. aureus. Antibiotic resistance is becoming a problem in the Internal Medicine ward. Formulation of a policy for hospital antibiotic use and an educational programme especially for junior doctors is required.


Comparative Safety Surveillance of Triple (IDA) Versus Dual Therapy (DA) in Mass Drug Administration for Elimination of Lymphatic Filariasis in Kenya: A Cohort Event Monitoring Study.
Dual diethylcarbamazine and albendazole (DA) therapy is the standard mass drug administration (MDA) regimen for lymphatic filariasis in Kenya. Following the recent World Health Organization recommendation, Kenya piloted triple therapy with ivermectin, diethylcarbamazine, and albendazole (IDA) in MDA. We conducted a community-based, observational, cohort event monitoring study to compare the types, frequency, severity, and predictors of adverse events following dual versus triple therapy in 20,421 eligible residents. Residents in Kilifi (n = 10,010) and Mombasa counties (n = 10,411) received DA and IDA through MDA campaigns, respectively. Adverse events were actively monitored through house-to-house visits on days 1, 2, and 7 after MDA. Any clinical events reported before and after MDA were cross-checked and verified to differentiate pre-existing events from MDA-associated adverse events. Overall, 5807 and 3102 adverse events were reported by 2839 and 1621 individuals in the IDA and DA groups, respectively. The incidence of experiencing one or more adverse events was significantly higher (p < 0.0001) in the IDA group (27.3%; 95% confidence interval [CI] 26.4-28.2) than in the DA group (16.2%; 95% CI 15.5-16.9). Dizziness (15.9% vs 5.9%) and drowsiness (10.1% vs 2.6%) were the most common adverse events and significantly higher in the IDA group compared with the DA group (p < 0.0001). Most adverse events were mild or moderate with a few severe cases (IDA = 0.05%; 95% CI 0.35-0.78, DA = 0.03%; 95% CI 0.14-0.60). Female sex, obesity, taking three or more diethylcarbamazine or ivermectin tablets, and having pre-existing clinical symptoms were significant predictors of adverse events following IDA treatment. Ivermectin, diethylcarbamazine, and albendazole as a combination is as safe and well tolerated as DA to use in MDA campaigns with no serious life-threatening adverse events. Systemic mild-to-moderate adverse events with a few severe cases and transient adverse events are more common with IDA treatment than with DA treatment. Hence, integrating pharmacovigilance into a MDA program is recommended for the timely detection and management of adverse events.


Diagnose ADHD disorder in children using convolutional neural network based on continuous mental task EEG.
Attention-Deficit/Hyperactivity Disorder (ADHD) is a chronic behavioral disorder in children. Children with ADHD face many difficulties in maintaining their concentration and controlling their behaviors. Early diagnosis of this disorder is one of the most important challenges in its control and treatment. No definitive expert method has been found to detect this disorder early. Our goal in this study is to develop an assistive tool for physicians to recognize ADHD children from healthy children using electroencephalography (EEG) based on a continuous mental task. We used EEG signals recorded from 31 ADHD children and 30 healthy children. In this study, we developed a deep learning model using a convolutional neural network that have had significant performance in image processing fields. For this purpose, we first preprocessed EEG signals to eliminate noise and artifacts. Then we segmented preprocessed samples into more samples. We extracted the theta, alpha, beta, and gamma frequency bands from each segmented sample and formed a color RGB image with three channels. Eventually, we imported the resulting images into a 13-layer convolutional neural network for feature extraction and classification. The proposed model was evaluated by 5-fold cross validation for train, evaluation, and test data and achieved an average accuracy of 99.06%, 97.81%, 97.47% for segmented samples. The average accuracy for subject-based test samples was 98.48%. Also, the performance of the model was evaluated using the confusion matrix with precision, recall, and f1-score metrics. The results of these metrics also confirmed the outstanding performance of the model. The accuracy, precision, recall, and f1-score of our model were better than all previous works for diagnosing ADHD in children. Based on these prominent and reliable results, this technique can be used as an assistive tool for the physicians in the early diagnosis of ADHD in children.


Pharmacokinetic study of a new testosterone-in-adhesive matrix patch applied every 2 days to hypogonadal men.
The present study assessed pharmacokinetic testosterone time profile and dose proportionality after application of a new matrix testosterone patch (30, 45, and 60 cm2 containing 0.5mg of testosterone per cm2). This open study was a single dose, three-period, crossover trial with a randomised treatment sequence in 24 hypogonadal men, consisting in a single 48-h application of two patches of 2x 30 cm2, 2x 45 cm2, 2x 60 cm2, separated by a 5-day wash-out. Testosterone concentrations were determined during patch application and after patch removal. Dose proportionality was assessed on baseline corrected, dose normalised parameters for C av,corr/D, C max,corr/D and AUC(0-48),corr/D. Testosterone concentrations rose during the first 9h following patch application, remained relatively sustained until 48 h and then decreased abruptly after patch removal, with a half-life of 1.3h. Testosterone levels were maintained above 3 ng/mL for 42-45 h with all patches. C av were 3.39, 4.03 and 4.58 ng/mL and Cmax were 4.33, 5.29 and 6.18 ng/mL according to the doses. AUC 0-48), C av and Cmax were dose dependent with mean ratios within the acceptance range (0.70-1.43). In conclusion, dose linearity was demonstrated between the different strengths of testosterone patches. Application resulted in dose proportional increases in serum T levels in hypogonadal men into the low to mid-normal range within the first hours and achieved steady state for 48 h. During this short term study with three consecutive patch applications, this patch was shown to be efficient, convenient and safe with excellent adhesiveness and skin tolerability, and with no cross-contamination to partner or to environment.


The effects of warm perineal compress on perineal trauma and postpartum pain: a systematic review with meta-analysis and trial sequential analysis.
In order to reduce the complications of perineal damage and the pain caused by it for the mother, this study was conducted to determine the effect of warm perineal compress on perineal trauma (1st-, 2nd-, 3rd-, and 4th-degree perineal tears), postpartum pain, intact perineum (primary outcomes), episiotomy, length of the second stage, and APGAR score at 1 and 5 min after childbirth (secondary outcome). PubMed, Scopus, Cochrane Central Register of Controlled Trials, Google Scholar, Web of Science, SID, Magiran, and ClinicalTrials.gov were searched to identify the relevant articles from inception to November 1, 2022, with language restriction (only English and Persian). A manual search was also performed. Risk of bias 2 (RoB2) and ROBIN-I were employed to evaluate the quality of the included papers. Meta-analysis was conducted using RevMan 5.3. Heterogeneity was assessed using I2. In cases with high heterogeneity, subgroup analysis was utilized based on the parity and ethnicity, and time of pain measurement after delivery also a random-effects model was used instead of a fixed-effects model. Trial sequential analysis (TSA) was performed for the primary outcomes. The certainty of evidence was assessed using the GRADE approach. A total number of 228 articles were found in databases. Of these articles, eighty-six were screened by title, 27 by abstract, and 21 by full text. Finally, 14 articles were included, of which ten were RCT and four were non-RCT. Meta-analysis results revealed that warm perineal compress significantly reduced perineal pain (RR 0.23, 95% CI 0.08-0.66; P = 0.0006), average pain (SMD - 0.73, 95% CI 1.23 to - 0.23; P = 0.004), second-degree perineal tear (RR 0.65, 95% CI 0.54-0.79; P˂0.00001), third-degree perineal tear (RR 0.32, 95% CI 0.15-0.67; P = 0.003), fourth-degree perineal tear (RR 0.11, 95% CI 0.01-0.87; P = 0.04), episiotomy (RR 0.63, 95% CI 0.46-0.86; P = 0.004), and intact perineum significantly increased (RR 3.06, 95% CI 1.79-5.22; P < 0.0001) compared to the control group. However, there was no statistically significant difference in terms of first-degree tear (RR 1.04, 95% CI 0.86-1.25; P = 0.72), length of the second stage of labor (MD - 0.60, 95% CI - 2.43 to 1.22; P = 0.52), the first minute (MD - 0.03, 95% CI - 0.07 to 0.02; P = 0.24) and the fifth minute Apgar score (MD - 0.02, 95% CI - 0.07 to 0.03; P = 0.46) between the two groups. Warm perineal compress administered during the second stage of labor reduce postpartum pain, second and third-degree perineal tears, and episiotomy rate while it increases the incidence of intact perineum compared to the control group.


Hyperrotatory paradoxic kyphosis.
A retrospective radiographic evaluation of 32 patients with hyperrotatory scoliosis accompanied by paradoxic hyperkyphosis, who were treated with posterior multilevel hook instrumentation. To give a three-dimensional analysis of this particular deformity and to evaluate the coronal, sagittal, and horizontal plane corrections in these specific curves. Lordoscoliosis with a severe rotational component produces paradoxic kyphosis in the sagittal plane. A vertebral derotational maneuver is essential to restore the normal sagittal alignment. Thirty-two patients were treated with posterior multilevel hook instrumentation. Nine patients had previously undergone anterior release and fusion. The derotational maneuver could be accomplished in 21 cases. The coronal Cobb angle and the extents of apical vertebral rotation, sagittal hyperkyphosis, upper and lower compensatory lordosis, and sagittal trunk balance were measured after an average follow-up period of 5 years and 9 months. The mean coronal deformity decreased from 89.9 degrees before surgery to 40.7 degrees. The mean preoperative hyperkyphosis was 70.9 degrees in the thoracic spine, 45.9 degrees in the thoracolumbar spine, and 55 degrees in the lumbar region. These values were reduced to 39.7 degrees, 6.8 degrees, and -15 degrees, respectively. The lateral spinal balance changed from -21.3 mm to -8.5 mm. The average rotational correction measured by the method of Jackson was 51% before surgery and 39% after surgery (correction: 23.5%). There was a positive correlation between the preoperative kyphosis angle and the apical rotation (r = 0.58) and between the decrease of kyphosis and the correction of the rotation (r = 0.67) in cases when the derotational maneuver could be accomplished. If the apex of the scoliosis and the kyphosis are on the same level, the vertebral hyperrotation is responsible for the sagittal malalignment. Satisfactory results can be achieved with posterior multilevel hook instrumentation.


Circulating miRNA Spaceflight Signature Reveals Targets for Countermeasure Development.
We have identified and validated a spaceflight-associated microRNA (miRNA) signature that is shared by rodents and humans in response to simulated, short-duration and long-duration spaceflight. Previous studies have identified miRNAs that regulate rodent responses to spaceflight in low-Earth orbit, and we have confirmed the expression of these proposed spaceflight-associated miRNAs in rodents reacting to simulated spaceflight conditions. Moreover, astronaut samples from the NASA Twins Study confirmed these expression signatures in miRNA sequencing, single-cell RNA sequencing (scRNA-seq), and single-cell assay for transposase accessible chromatin (scATAC-seq) data. Additionally, a subset of these miRNAs (miR-125, miR-16, and let-7a) was found to regulate vascular damage caused by simulated deep space radiation. To demonstrate the physiological relevance of key spaceflight-associated miRNAs, we utilized antagomirs to inhibit their expression and successfully rescue simulated deep-space-radiation-mediated damage in human 3D vascular constructs.


Prescription-free consultation: A cross-sectional study in general practice.
In 2005, 10% of consultations in France ended without a prescription. In 2019, a review of the literature found 30 to 70% of prescription-free consultations in Northern Europe and 10 to 22% in Southern Europe and underlined the scarcity of quantitative data. Different factors contribute to this heterogeneity, such as product availability and status, modes of management, distribution channels, clinical practice recommendations, public policies targeting certain classes, etc. The main objective of our study was to quantify the rate of prescription-free consultations in general practice in France in 2021. The secondary objective was to characterize prescription-free consultations and analyze their determinants. This was a quantitative observational study conducted using self-questionnaires among patients in medical practices in Auvergne. Out of 540 questionnaires, the rate of prescription-free consultations was 24% (95% CI [20.11-27.41]). Prescription-free consultations were for prevention, administrative problems, and gestures. The limiting factors are "feeling a need for a medication" (OR=0,006), "not knowing if a medication is needed" (OR=0.11) and "consultations for acute reasons" (OR=0.33). Acute consultations limit prescription-free consultations. General practitioners (GPs) probably overestimate patients' expectation of drug prescription. The French GP must be supported in their decision to not prescribe drugs. This is a long-term investment of time, to educate patients and avoid new consultations for acute reasons. A tool to help doctors manage non-prescription during acute consultations will be created in a future study in France.


Novel strategies for the treatment of grass pollen-induced allergic rhinitis.
Allergic rhinitis (AR) affects over 20% of the population of Europe and the United States. Allergen immunotherapy (AIT) is currently the only form of treatment that affects symptoms and modifies the progression of disease. Established forms of AIT include subcutaneous (SCIT) and sublingual (SLIT) immunotherapy and are widely effective, yet only 2-9% of eligible patients undergo therapy, likely due to the long duration of treatment. As a result, novel, faster forms of AIT are currently under development. This article provides an overview of AR and summarises the efficacy and mechanisms of established forms of AIT, highlighting the current drawbacks. We discuss novel strategies of AIT that have been developed in an attempt to tackle these limitations, including epicutaneous, intradermal and intralymphatic immunotherapy (ILIT), focusing on ILIT, the treatment that has been most comprehensively assessed. Current strategies to treat AR suffer from a poor safety profile and, importantly, lack of adherence. ILIT is a faster and safer form of AIT, with a treatment regime of only 12 weeks. Further validation is required, but ILIT, with its short and comparatively inexpensive protocol, has the potential to offer disease-modifying therapy to a larger number of patients.


[Recovery from thermal damage of mammalian cells fixed by treatment with a hypertonic sodium chloride solution].
The survival of Chinese hamster cell V79-4 after hyperthermic treatment (42 degrees C, 40 minutes) in the exponential growth phase considerably increases with the duration of holding them in the growth medium at 37 degrees C before hypertonic salt treatment (1.5 M NaCl, 15 minutes). The experimental data are interpreted as a recovery of mammalian cells from thermal lesions, whose lethal action manifests itself at high salt concentrations.


Evaluation of the Leishmania recombinant K39 antigen as a diagnostic marker for canine leishmaniasis and validation of a standardized enzyme-linked immunosorbent assay.
Canine infections with Leishmania infantum are important as a cause of serious disease in the dog and as a reservoir for human visceral leishmaniasis (VL). Accurate diagnosis of canine infections is essential to the veterinary community and for VL surveillance programs. A standardized ELISA using a purified recombinant antigen (rK39) specific to VL was compared to the immunofluorescent antibody test (IFAT) as the standard. The ELISA was developed, optimized and evaluated using sera from 6368 dogs. The standardized ELISA and IFAT results were highly concordant. The timing and pattern of ELISA and IFAT seroconversion in dogs followed prospectively after natural infections were very similar. Antibodies reacting with rK39 were more common in asymptomatic canine infections than reported for subclinical human VL. The rK39 ELISA is a relatively simple and rapid assay for assessing the infection status of dogs, and is an alternative to IFAT, especially when screening large numbers of samples.


Automated solid-phase synthesis of a β-(1,3)-glucan dodecasaccharide.
β-Glucans are a group of structurally heterogeneous polysaccharides found in bacteria, fungi, algae and plants. β-(1,3)-D-Glucans have been studied in most detail due to their impact on the immune system of vertebrates. The studies into the immunomodulatory properties of these glucans are typically carried out with isolates that contain a heterogeneous mixture of polysaccharides of different chain lengths and varying degrees of branching. In order to determine the structure-activity relationship of β-(1,3)-glucans, access to homogeneous, structurally-defined samples of these oligosaccharides that are only available through chemical synthesis is required. The syntheses of β-glucans reported to date rely on the classical solution-phase approach. We describe the first automated solid-phase synthesis of a β-glucan oligosaccharide that was made possible by innovating and optimizing the linker and glycosylating agent combination. A β-(1,3)-glucan dodecasaccharide was assembled in 56 h in a stereoselective fashion with an average yield of 88% per step. This automated approach provides means for the fast and efficient assembly of linker-functionalized mono- to dodecasaccharide β-(1,3)-glucans required for biological studies.


[Specific features of QRS-complex identification algorithms for real-time ECG systems].
The paper reviews the existing methods for identifying QRS complexes. An attempt is made to make a well-defined classification of available algorithms in an approach to QRS detection. Emphasis is laid on the consideration of specific requirements for such algorithms by computer-aided real-time ECG systems. A task of choice of the most suitable method is formulated. An algorithm based on the well-known principles of frequency-time detection is proposed as an alternative solution of this task. The algorithm makes it possible to single out QRS complexes from real-time ECG and to effectively make a digital signal processing by available optimized libraries. The method initially used in the Matlab package has been integrated within the laboratory computerized ECG system.


[Sarcoidosis and berylliosis].
Sarcoidosis and berylliosis (chronic beryllium disease, CBD) are granulomatous diseases and are phenocopies which cannot be differentiated based on the clinical presentation. Whereas for sarcoidosis the eliciting agent is unknown, for berylliosis an exposure to beryllium (mostly as occupational exposure) can be confirmed that therefore induces a sensitization against beryllium. The diagnosis is generally made in patients with a typical clinical presentation, the histological proof of a non-necrotizing granuloma and the exclusion of other diseases causing granulomas. In most cases, granulomas can be detected in the lungs and/or (intrathoracic) lymph nodes. The proof of sensitization to beryllium for the differential diagnosis can be performed with a so-called beryllium lymphocyte proliferation test in peripheral mononuclear blood cells or cells from a bronchoalveolar lavage. The objectives of treatment are avoidance of functional organ impairment and symptom control. Immunosuppressive therapy (initially mostly with corticosteroids) and supportive measures can prove beneficial; however, in many cases clinical observation can be sufficient because of stable disease or spontaneous resolution. In addition, further beryllium exposure must be avoided, which mostly necessitates a change of the workplace.


Anti-tumor compound RY10-4 suppresses multidrug resistance in MCF-7/ADR cells by inhibiting PI3K/Akt/NF-κB signaling.
RY10-4, an anti-tumor agent, exerts cytotoxicity to various human cancer cell lines. However, few studies reported the effect of combined application of RY10-4 and chemotherapeutic drugs against cancer cells with multidrug resistance (MDR). In this study, P-glycoprotein (P-gp), which is reported to mediate MDR to anti-cancer drugs, was proved to be overexpressed in the adriamycin (ADR)-resistant human breast cancer cells, namely MCF-7/ADR cells. Furthermore, RY10-4 application resulted in a downregulation of P-gp in MCF-7/ADR cells, thus leading to higher chemosensitivity to ADR. Our study further demonstrated that the MDR phenomenon was under the control of the PI3K/Akt/NF-κB pathway, which was suppressed by RY10-4, leading to MDR reversal effects in MCF-7/ADR cells. In vivo, MCF-7/ADR cells were effectively suppressed by the combined ADR/RY10-4 treatment compared with the ADR-alone treatment. Taken together, these results demonstrated that RY10-4 reverses the MDR phenotype in MCF-7/ADR cells by suppressing the PI3K/Akt/NF-κB pathway.


[Effect of inhibitors of free radical processes on the "dark" paramagnetic centers of the melanoprotein granules of the pigment epithelium of the eye].
Effect of three inhibitors of free radical processes (IFRP) differing in antiradical activity (2-tret. butyl-6-methyl-3-oxipyridin, 2-ethyl-6-methyl-3-oxipyridin and 3-oxipyridin) on paramagnetic centres of melanoprotein granules of pigment epithelium was studied by ESR method at room temperature. It was shown that IFRP decreased the dark signal and that the reaction of paramagnetic particles dissociation proceeded according to the equation of the first order reaction. The rate constants of these reactions were calculated. It was found that the relative amount of reacting and non-reacting paramagnetic particles with the inhibitor depended on the nature and concentration of IFRP.


[Role of 5-bromodeoxyuridine in the formation of sister chromatid exchanges in human lymphocytes exposed to gamma-irradiation at the presynthetic stage of the mitotic cycle].
The formation of SCE was studied in human lymphocytes irradiated at the presynthetic stage of the cell cycle in the presence or absence of 5-bromodeoxyuridine. The results obtained showed that 5-bromodeoxyuridine present in the culture medium at the time of exposure or during the postirradiation period increased the yield of SCE. It is suggested that 5-bromodeoxyuridine exerts its effect through interfering with DNA repair.


Evolutionarily Distinctive Transcriptional and Signaling Programs Drive Human Germ Cell Lineage Specification from Pluripotent Stem Cells.
Germline specification underlies human reproduction and evolution, but it has proven difficult to study in humans since it occurs shortly after blastocyst implantation. This process can be modeled with human induced pluripotent stem cells (hiPSCs) by differentiating them into primordial germ cell-like cells (hPGCLCs) through an incipient mesoderm-like cell (iMeLC) state. Here, we elucidate the key transcription factors and their interactions with important signaling pathways in driving hPGCLC differentiation from iPSCs. Germline competence of iMeLCs is dictated by the duration and dosage of WNT signaling, which induces expression of EOMES to activate SOX17, a key driver of hPGCLC specification. Upon hPGCLC induction, BMP signaling activates TFAP2C in a SOX17-independent manner. SOX17 and TFAP2C then cooperatively instate an hPGCLC transcriptional program, including BLIMP1 expression. This specification program diverges from its mouse counterpart regarding key transcription factors and their hierarchies, and it provides a foundation for further study of human germ cell development.


Chronic Postsurgical Pain.
Chronic postsurgical pain (CPSP) is defined as a persistent pain state that exists more than 2 months postoperatively and cannot be explained by other causes such as recurrence of disease, apparent inflammation, or other nonsurgical related factors. CPSP is a type of persistent pain condition that often complicates recovery from surgical procedures. It is thought to be caused by surgical nerve injury, but the fact that an identifiable nerve injury can be found in only one-third of CPSP patients suggests that the problem may be far more complex than a simple surgically created nerve injury. Certain surgical procedures report a high incidence of CPSP, helping to isolate likely candidates for this problem, but instituting preventative measures and identifying a treatable source of pain continues to be elusive. Some progress has been made in the areas of prevention and treatment.


Distribution and coassociations of trace elements in soft tissue and byssus of Mytilus galloprovincialis relative to the surrounding seawater and suspended matter of the southern part of the Korean Peninsula.
The concentrations of Cd, Co, Cu, Cr, Fe, Hg, Mn, Ni, Pb, Sn, Ti and Zn were analyzed by AAS, ICP MS and AFS in soft tissues and byssal threads of Mytilus galloprovincialis from Masan Bay and Ulsan Bay, Korea. Spatial variations in metal concentrations were found. The levels of Cd, Pb, Hg, Cu, Zn, Co and Mn were very high in the mussels from Ulsan Bay (Sts. U1, U2) and comparable with elevated concentrations of these elements in Mytilus sp. reported to date for other geographical areas. Seasonal differences in some metal concentrations were also observed. These variations may be caused by factors such as: a large difference in seawater temperature, food supply for the mussel population and/or freshwater runoff of particulate metal to the coastal water and weight changes brought about by gonadal development and the release of sexual products. Pb, Cu, Zn, Co, Ni, Fe and Mn were more enriched in byssal threads than in the soft tissues, hence the byssus seems to be more sensitive in reflecting the availabilities of trace metals in the ambient waters. Concentrations of trace metals varied with respect to the size of mussels and season, depending on many factors like sexual development, and seawater temperature, etc. The levels of some trace metals in seawater, especially in suspended matter were correlated significantly with those in soft tissues and byssal threads. There were spatial variations in metal concentrations in the soft tissue and byssus attributed to different sources of trace elements located near the sampling sites. There were significant relationships between concentrations of some metals (Cd, Cu, Pb, and Zn) in mussel soft tissues and byssal threads and suspended matter. This suggests that M. galloprovincialis can be used as a sensitive biomonitor for the availabilities of trace elements in the coastal waters off Korea.


Assessment of different methods in analyzing motor vehicle emission factors.
To explore the emission characteristics of vehicle's pollutants is of great significance to prevent and control the diffusion of pollutants. Limited by geographic location and economic condition, the model- and guideline-based studies on vehicle's emission factor have become more concerned measures than the actual measurement. By analyzing the actual operating conditions of motor vehicles, this study obtains the emission factors of typical pollutants from different motor vehicles by adopting international vehicle emission (IVE) model and guideline method, respectively. Furthermore, the resulting emission factors by the above methods were compared and analyzed with on-road method. The results show that: (1) the emission factors of vehicle pollutants change regularly with velocity, emission standard, and accumulated mileage. Taking CO as an example, its emission factor shows a downward trend with the increase of velocity and emission standard and an upward trend with the increase of accumulated mileage; (2) compared with the actual measurement, the vehicle emission factor obtained by the guideline method has a large error, while the IVE model is close to the actual.


T-2 and HT-2 toxin analysis in cereals and cereal products following IAC cleanup and determination via GC-ECD after derivatization.
The authors present a new and sensitive method for the determination of T-2- und HT-2 Toxin in cereals and cereal products in the low ppb level. A representative part of the cereal sample is extracted with a mixture of methanol-water (90:10) and the extract is cleaned on the commercially available immunoaffinity column T-2test™ (IAC), eluted with methanol, derivatized by pentafluorpropionic anhydride (PFPA) and measured on a GC-ECD. The method has been successfully validated on wheat, rye and oats. The recovery rates with wheat and rye endowed on a level of 50 ppb and with 85 ppb naturally contaminated oats were 71-115% with a coefficient of variation of 5.7-19.5%. The detection limits of the method with a signal to noise level of 3:1 were 1.5-2.3 μg/kg for HT-2 and 1.1-1.7 μg/kg for T-2 toxin.


A survey of practice of tracheal intubation without muscle relaxant in paediatric patients.
Because of the renewed interest in intubation in children without relaxants, over a period of 1 month, the anaesthesiologists of five paediatric universitary teaching hospitals were asked to complete a questionnaire each time they performed a tracheal intubation without muscle relaxant. Intubating conditions were assessed with five items. Each item was graded on a four-point scale. Intubating conditions were judged acceptable when all items scored 2 or less. Episodes of oxygen desaturation and failed intubations were noted. Data are expressed as mean +/- SD (extremes). Five hundred and two questionnaires were completed during the study period. Children were aged 61 +/- 50 (1-180) months old. Induction of anaesthesia was performed with sevoflurane for 62.6% of the children (endtidal concentration 5.9 +/- 1.5%) and propofol for 28.9% (dose 5.8 +/- 4.2 mg x kg(-1). Opioids were associated with these hypnotics in 53.2% of the children. Tracheal intubation was successful in 87.1% of the children. Sevoflurane produced better intubating conditions than propofol. Sevoflurane requirements for tracheal intubation may be higher in infants aged less than 6 months old than in older children. A severe decrease in SpO2 (< or = 90%) was observed in 15.9% of the infants aged less than 1 year old and in 1.7% of the children, respectively (P < 0.0001). Sevoflurane is the most commonly used agent for tracheal intubation without relaxants with higher doses being required in infants aged less than 6 months. Propofol, even with opioids, was not so successful.


Basal ganglia ischaemic infarction after thrombectomy: cognitive impairment at acute stage.
After successful mechanical thrombectomy for middle cerebral artery occlusion, basal ganglia infarction is commonly detectable. Whilst the functional outcome of these patients is often good, less knowledge is available about the cognitive outcome. The aim of our study was to assess the presence of cognitive impairment within 1 week after thrombectomy. In all, 43 subjects underwent a general cognitive assessment using the Montreal Cognitive Assessment and an extensive battery of tests. Patients were classified as cognitively impaired (CImp) or not (noCImp) according to a Montreal Cognitive Assessment score below 18. Cognitively impaired and noCImp subjects did not differ either in their National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) at admittance, or in their Fazekas score and Alberta Stroke Program Early Computed Tomography Score. At discharge, CImp subjects showed higher scores than noCImp subjects on NIHSS (p = 0.002) and mRS (p < 0.001). The percentage of pathological performances on each neuropsychological test in the whole sample and in CImp and noCImp patients shows a similar cognitive profile between the groups. Some patients who underwent thrombectomy experienced a detectable cognitive impairment that probably led to worse NIHSS and mRS. The neuropsychological profile of such cognitive impairment at the acute stage consists of wide deficits in numerous cognitive domains, suggesting that basal ganglia damage may lead to complex functional impairments.


Protein microcrystallography using synchrotron radiation.
The progress in X-ray microbeam applications using synchrotron radiation is beneficial to structure determination from macromolecular microcrystals such as small in meso crystals. However, the high intensity of microbeams causes severe radiation damage, which worsens both the statistical quality of diffraction data and their resolution, and in the worst cases results in the failure of structure determination. Even in the event of successful structure determination, site-specific damage can lead to the misinterpretation of structural features. In order to overcome this issue, technological developments in sample handling and delivery, data-collection strategy and data processing have been made. For a few crystals with dimensions of the order of 10 µm, an elegant two-step scanning strategy works well. For smaller samples, the development of a novel method to analyze multiple isomorphous microcrystals was motivated by the success of serial femtosecond crystallography with X-ray free-electron lasers. This method overcame the radiation-dose limit in diffraction data collection by using a sufficient number of crystals. Here, important technologies and the future prospects for microcrystallography are discussed.


Efficacy comparison of laparoscopic sleeve gastrectomy in type 2 diabetes patients with a BMI 30-34.9 kg/m2 versus BMI < 30 kg/m2.
Laparoscopic sleeve gastrectomy (LSG) is safe and effective in type 2 diabetes mellitus (T2DM) with body mass index (BMI) ≥ 35 kg/m2. However, the effect and safety of LSG in the treatment of T2DM patients with BMI less than 35 kg/m2, especially in patients with BMI less than 30 kg/m2, are still debatable. A total of 51 T2DM patients with BMI less than 35 kg/m2 treated successfully with LSG were included in our study. All patients were divided into two groups for subgroup analysis, namely group A (BMI 23.23-29.97 kg/m2) and group B (BMI 30.0-34.9 kg/m2). The weight loss and diabetic characteristics of LSG in the two groups at 3 months, 6 months, and 12 months after operation were compared, respectively. In group A, the complete remission rates of T2DM were 20%, 36%, and 44% at 3, 6, and 12 months after operation, respectively. In group B, the complete remission rates of T2DM were 30.8%, 61.5%, and 88.5% at 3, 6, and 12 months after operation, respectively. Besides, none of the patients with a duration more than 15 years achieved complete remission. For T2DM patients with BMI < 30 kg/m2 at 12 months after LSG, the complete remission rate of T2DM was 15.4% in patients with ABCD scores ≤ 2, and the complete remission rate of T2DM was 100% in patients with ABCD scores ≥ 5. LSG is safe and effective for T2DM patients with BMI less than 35 kg/m2 in the short-term. However, the complete remission rate of T2DM in patients with BMI less than 30 kg/m2 is far from the diabetes patients with BMI at 30-34.9 kg/m2.


Multi-site clustering and nested feature extraction for identifying autism spectrum disorder with resting-state fMRI.
Brain functional connectivity (FC) derived from resting-state functional magnetic resonance imaging (rs-fMRI) has been widely employed to study neuropsychiatric disorders such as autism spectrum disorder (ASD). Existing studies usually suffer from (1) significant data heterogeneity caused by different scanners or studied populations in multiple sites, (2) curse of dimensionality caused by millions of voxels in each fMRI scan and a very limited number (tens or hundreds) of training samples, and (3) poor interpretability, which hinders the identification of reproducible disease biomarkers. To this end, we propose a Multi-site Clustering and Nested Feature Extraction (MC-NFE) method for fMRI-based ASD detection. Specifically, we first divide multi-site training data into ASD and healthy control (HC) groups. To model inter-site heterogeneity within each category, we use a similarity-driven multiview linear reconstruction model to learn latent representations and perform subject clustering within each group. We then design a nested singular value decomposition (SVD) method to mitigate inter-site heterogeneity and extract FC features by learning both local cluster-shared features across sites within each category and global category-shared features across ASD and HC groups, followed by a linear support vector machine (SVM) for ASD detection. Experimental results on 609 subjects with rs-fMRI from the ABIDE database with 21 imaging sites suggest that the proposed MC-NFE outperforms several state-of-the-art methods in ASD detection. The most discriminative FCs identified by the MC-NFE are mainly located in default mode network, salience network, and cerebellum region, which could be used as potential biomarkers for fMRI-based ASD analysis.


A statistical modeling approach based on the small-scale field trial and meteorological data for preliminary prediction of the impact of low temperature on Eucalyptus globulus trees.
Eucalyptus trees are important for industrial forestry plantations because of their high potential for biomass production, but their susceptibility to damage at low temperatures restricts their plantation areas. In this study, a 6-year field trial of Eucalyptus globulus was conducted in Tsukuba, Japan, which is the northernmost reach of Eucalyptus plantations, and leaf damage was quantitatively monitored over four of six winters. Leaf photosynthetic quantum yield (QY) levels, an indicator of cold stress-induced damage, fluctuated synchronously with temperature in the winters. We performed a maximum likelihood estimation of the regression model explaining leaf QY using training data subsets for the first 3 years. The resulting model explained QY by the number of days when the daily maximum temperature was below 9.5 °C over approximately the last 7 weeks as an explanatory variable. The correlation coefficient and coefficient of determination of prediction by the model between the predicted and observed values were 0.84 and 0.70, respectively. The model was then used to perform two kinds of simulations. Geographical simulations of potential Eucalyptus plantation areas using global meteorological data from more than 5,000 locations around the world successfully predicted an area that generally agreed with the global Eucalyptus plantation distribution reported previously. Another simulation based on meteorological data of the past 70 years suggested that global warming will increase the potential E. globulus plantation area in Japan approximately 1.5-fold over the next 70 years. These results suggest that the model developed herein would be applicable to preliminary predictions of E. globulus cold damage in the field.


Fluoroscopically controlled examination of the upper gastrointestinal tract using low density barium. A review of 139 endoscopically proven lesions.
120 of 139 endoscopically verified lesions were diagnosed by fluoroscopically controlled examination of the upper gastrointestinal tract (sensitivity 86%). The incidence of false negative results was 19/139 (14%). The lesions most frequently missed were ulcerations of 1 or 2 mm in size, or lesions obscured by gastric contents. All 16 malignancies were diagnosed radiologically. It is concluded that with proper fluoroscopic-radiographic technique the sensitivity of fluoroscopically controlled examination of the upper gastrointestinal tract is comparable to (or better than) that of double contrast studies.


Multifarious Responses of Forest Soil Microbial Community Toward Climate Change.
Forest soils are a pressing subject of worldwide research owing to the several roles of forests such as carbon sinks. Currently, the living soil ecosystem has become dreadful as a consequence of several anthropogenic activities including climate change. Climate change continues to transform the living soil ecosystem as well as the soil microbiome of planet Earth. The majority of studies have aimed to decipher the role of forest soil bacteria and fungi to understand and predict the impact of climate change on soil microbiome community structure and their ecosystem in the environment. In forest soils, microorganisms live in diverse habitats with specific behavior, comprising bulk soil, rhizosphere, litter, and deadwood habitats, where their communities are influenced by biotic interactions and nutrient accessibility. Soil microbiome also drives multiple crucial steps in the nutrient biogeochemical cycles (carbon, nitrogen, phosphorous, and sulfur cycles). Soil microbes help in the nitrogen cycle through nitrogen fixation during the nitrogen cycle and maintain the concentration of nitrogen in the atmosphere. Soil microorganisms in forest soils respond to various effects of climate change, for instance, global warming, elevated level of CO2, drought, anthropogenic nitrogen deposition, increased precipitation, and flood. As the major burning issue of the globe, researchers are facing the major challenges to study soil microbiome. This review sheds light on the current scenario of knowledge about the effect of climate change on living soil ecosystems in various climate-sensitive soil ecosystems and the consequences for vegetation-soil-climate feedbacks.


Tryptase from human mast cells does not activate purified human Hageman factor.
The effect of tryptase, a neural protease released from human lung mast cell secretory granules, on purified human Hageman Factor (Factor XII) was examined. No increase in Hageman Factor enzymatic activity was detected after incubation with tryptase at 37 degrees C; activation of Hageman Factor by bovine trypsin served as a positive control. Furthermore, pre-incubation of Hageman Factor with tryptase did not diminish the subsequent activation of Hageman Factor by trypsin. Polyacrylamide gel electrophoresis was also performed to show that incubation with tryptase does not alter the molecular weight of Hageman Factor. Therefore, tryptase neither activates nor destroys human Hageman Factor.


BTB and CNC homology 1 (Bach1) induces lung cancer stem cell phenotypes by stimulating CD44 expression.
Growing evidence suggests that cancer stem cells (CSCs) are responsible for cancer initiation in tumors. Bach1 has been identified to contribute to several tumor progression, including lung cancer. The role of Bach1 in CSCs remains poorly known. Therefore, the function of Bach1 on lung CSCs was focused currently. The expression of Bach1, CD133, CD44, Sox2, Nanog and Oct4 mRNA was assessed using Real-Time Quantitative Reverse Transcription PCR (RT-qPCR). Protein expression of Bach1, CD133, CD44, Sox2, Nanog, Oct4, p53, BCL2, BAX, p-p38, p-AKT1, c-Fos and c-Jun protein was analyzed by western blotting. 5-ethynyl-29-deoxyuridine (EdU), colony formation, Flow cytometry analysis and transwell invasion assay were carried out to analyze lung cancer cell proliferation, apoptosis and invasion respectively. Tumor sphere formation assay was utilized to evaluate spheroid capacity. Flow cytometry analysis was carried out to isolate CD133 or CD44 positive lung cancer cells. The relationship between Bach1 and CD44 was verified using ChIP-qPCR and dual-luciferase reporter assay. Xenograft tumor tissues were collected for hematoxylin and eosin (HE) staining and IHC analysis to evaluate histology and Ki-67. The ratio of CD44 + CSCs from A549 and SPC-A1 cells were significantly enriched. Tumor growth of CD44 + CSCs was obviously suppressed in vivo compared to CD44- CSCs. Bach1 expression was obviously increased in CD44 + CSCs. Then, via using the in vitro experiment, it was observed that CSCs proliferation and invasion were greatly reduced by the down-regulation of Bach1 while cell apoptosis was triggered by knockdown of Bach1. Loss of Bach1 was able to repress tumor-sphere formation and tumor-initiating CSC markers. A repression of CSCs growth and metastasis of shRNA-Bach1 was confirmed using xenograft models and caudal vein injection. The direct interaction between Bach1 and CD44 was confirmed by ChIP-qPCR and dual-luciferase reporter assay. Furthermore, mitogen-activated protein kinases (MAPK) signaling pathway was selected and we proved the effects of Bach1 on lung CSCs were associated with the activation of the MAPK pathway. As manifested, loss of Bach1 was able to repress p-p38, p-AKT1, c-Fos, c-Jun protein levels in lung CSCs. Inhibition of MAPK signaling remarkably restrained lung CSCs growth and CSCs properties induced by Bach1 overexpression. In summary, we imply that Bach1 demonstrates great potential for the treatment of lung cancer metastasis and recurrence via activating CD44 and MPAK signaling.


Phase II and pharmacokinetic study of GL331 in previously treated Chinese gastric cancer patients.
A phase II and pharmacokinetic study was designed to assess the efficacy and toxicity profile of an epidophyllotoxin analogue, GL331, in previously treated Chinese gastric cancer patients, with concurrent pharmacokinetic evaluation of the drug's metabolism. GL331 was given at 200 mg/m(2) as a daily 3-h infusion for 5 days every 4 weeks. Enrolled in the study were 15 patients. One patient died from neutropenic sepsis before evaluation, one patient did not receive the full dose for reasons unrelated to GL331, nine patients had progressive disease with a median survival of 80 days, and five had stable disease with a median survival of 240 days. Grade 3 and 4 myelosuppression occurred in 10 of the 15 patients, with one death from neutropenic sepsis. This patient's peak GL331 concentration was 16.8 microg/ml, which was high compared to the mean peak drug concentration of 6+/-4.1 microg/ml. The mean systemic GL331 clearance was 12.1+/-7.2 l/h per m(2), much lower than 23.3+/-8.2 l/h per m(2) found in the phase I trial. Topoisomerase IIalpha was determined by immunohistochemistry and overexpression was detected in 3 of 11 specimens. GL331 was ineffective at this dose and schedule in this group of patients in spite of adequate blood levels of the drug.


Spexin ameliorates skeletal muscle insulin resistance through activation of GAL2 receptor.
Skeletal muscle is a principal tissue involved in energy expenditure and glucose metabolism. Although the results of our and other studies show that spexin could decrease food intake and obesity, the specific metabolic effect of spexin on glucose metabolism of skeletal muscle is still unclear. The aim of this study is to investigate whether spexin might mitigate obesity-induced insulin resistance in skeletal muscles and to explore its underlying mechanisms. The high fat diet-fed mice were treated with 50 μg/kg/d spexin for 21 consecutive days, and the differentiated myotubes of L6 were treated with spexin (200, 400, 800 nM) in the absence or presence of M871 (800 nM) for 12 h respectively. Besides, the galanin type 2 (GAL2) receptor knockdown myotubes were treated with 800 nM spexin for 12 h in this study. The present findings showed that spexin reversed hyperglycemia and glucose intolerance as well as insulin intolerance and insulin resistance in the mice fed with high fat diet. Furthermore, spexin markedly augmented the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) expression and deacetylation, and further triggered glucose transporter 4 (GLUT4) expression and trafficking in myotubes through p38 mitogen-activated protein kinase (P38MAPK) and protein kinase B (AKT) activation. More importantly, the elevation of glucose consumption related genes by spexin were abolished by GAL2 receptor antagonist or silencing of GAL2 receptor in myotubes. In conclusion, our findings provide a novel insight that spexin can protect against insulin resistance and increase glucose consumption in skeletal muscles mainly through activation of GAL2/GLUT4 signal pathway. Spexin might therefore be a novel therapeutic target for hyperglycemia and insulin resistance in clinic.


Quantitative fetal fibronectin predicts preterm birth in women with bulging fetal membranes.
To assess the predictive value of quantitative fetal fibronectin (fFN) concentration in cervicovaginal fluid for spontaneous preterm birth in women with bulging fetal membranes. This was a prospective observational study from five UK tertiary centres of a cohort of women with singleton pregnancy and bulging fetal membranes presenting between 18 and 32 weeks of gestation (n=62), in the period 2010-2014. fFN concentrations in cervicovaginal fluid were measured both quantitatively and qualitatively at presentation in all women. Predictive statistics and receiver operating characteristic (ROC) curves were calculated for both tests to predict spontaneous preterm birth within 14 days from testing and before 34 weeks of gestation. 62 eligible women with bulging fetal membranes were recruited from screening of 2571 women at high risk of preterm birth. The median gestational age was 24(+0) (LQ-UQ, 21(+2)-25(+3)) at presentation and 34(+4) (25(+2)-39(+0)) at delivery, with a median time from testing to delivery of 58 days (17-110). Concentration of quantitative fFN at presentation correlated negatively with time to delivery (Spearman's rs=-0.615, p<0.001). The area under the ROC curve for quantitative fFN testing was 0.81 (95% CI 0.69-0.94) for prediction of spontaneous preterm birth within 14 days, and 0.84 (0.73-0.95) before 34 weeks of gestation. Quantitative fFN has a role in predicting spontaneous preterm birth even in women with bulging fetal membranes, suggesting that fFN leakage could potentially be an active process. This may aid the clinical management of this high-risk group in the future.


Small-molecule delivery by nanoparticles for anticancer therapy.
Using nanoparticles for the delivery of small molecules in anticancer therapy is a rapidly growing area of research. The advantages of using nanoparticles for drug delivery include enhanced water solubility, tumor-specific accumulation and improved antitumor efficacy, while reducing nonspecific toxicity. Current research in this field focuses on understanding precisely how small molecules are released from nanoparticles and delivered to the targeted tumor tissues or cells, and how the unique biodistribution of the drug-carrying nanoparticles limits toxicity in major organs. Here, we discuss existing nanoparticles for the delivery of small-molecule anticancer agents and recent advances in this field.


The penetration of the embedding medium methyl methacrylate in undecalcified bone.
Cutting artifacts in microtome sections prepared from undemineralized methyl methacrylate embedded bone are due to the almost complete absence of methacrylate in the intercellular compartment of the bone tissue, the soft tissues being fully impregnated with the polymer. The osteocyte system is only partially penetrated by methacrylate.


The influence of vitamin B-6 on cystathioninuria in premature infants.
The amount of cystathionine excreted in the urine of premature infants, ages 10 to 17 days, decreases after oral administration of 40 mg vitamin B-6 daily. Thus, it can be speculated that in vivo cystathionase of premature infants may be induced or activated by pyridoxine.


Human health risks of Pb and As exposure via consumption of home garden vegetables and incidental soil and dust ingestion: a probabilistic screening tool.
The consumption of home grown vegetables may represent a significant exposure pathway for arsenic (As) and lead (Pb) relative to direct incidental ingestion of soil, thus a probabilistic screening tool for estimating these exposures was developed using regression models relating co-located soil and home garden (HG) vegetable concentrations of Pb and As established from multiple independent studies and 2-dimensional Monte Carlo analyses. For high-quantity consumers of HG vegetables (i.e., the upper 95th percentile of consumers in the general population), the HG consumption pathway can be as significant as incidental soil and dust ingestion for inorganic As and, therefore, should be considered when developing generic health-based soil criteria in residential settings. Predicted Pb Hazard Quotient (HQ) estimates among young children resulting from HG consumption were 4- to 10-fold lower than exposures resulting from direct incidental soil and dust ingestion. The difference in soil/dust ingestion rates used to characterize young children (the 95th percentile of 202 mg/d) versus a lifetime residential receptor (the 95th percentile of 30 mg/d) was a primary factor contributing to the relative differences observed between HQ and incremental lifetime cancer risk (ILCR) resulting from these two exposure pathways for lead Pb and inorganic arsenic As, respectively.


Influence of cut-points on patterns of accelerometry-measured free-living physical activity in rural and urban black South African women.
We describe the effect of 2 different accelerometer cut-points on physical activity (PA) patterns in rural and urban black South African women. Hip-mounted uni-axial accelerometers were worn for 6 to 7 days by rural (n = 272) and urban (n = 16) participants. Twenty-hour (4 AM to 12 AM) PA counts (cts) and volumes (min·day⁻¹) were extracted: sedentary (SED, <100 cts·min⁻¹), light (100-759 cts·min⁻¹), moderate-1 (MOD1, 760-1951 cts·min⁻¹), moderate-2 to vigorous (MOD2VG, ≥1952 cts·min⁻¹), and bouts ≥10 min for ≥760 cts·min⁻¹ (MOD1VGbt) and ≥1952 cts·min⁻¹ (MOD2VGbt). Valid data were obtained from 263 rural women and 16 urban women. Total counts and average counts were higher (+80,399 cts·day⁻¹, +98 cts·min⁻¹.day⁻¹) (P < .01), SED lower (-61 min·day⁻¹, P = .0042), MOD1 higher (+65 min·day⁻¹, P < .0001), and MOD1VGbt higher (+19 min·day⁻¹, P = .0179) in rural women compared with urban women. Estimated adherence (≥30 min·day⁻¹ for 5 days·wk⁻¹) was 1.4-fold higher in rural women than urban women for MOD-1VGbt, but 3.3-fold higher in urban women than rural women for MOD2VGbt. Rural women accumulate greater amounts of PA than urban women within a particular count band. Depending on which moderate PA cut-point was used to estimate PA public health adherence, rural women could be classified as less physically active than urban women.


Linkages and associations to intermediate phenotypes underlying asthma and allergic disease.
Considerable effort and expense has been expended in attempts to detect specific polymorphisms in genetic loci contributing to susceptibility to allergic diseases. Increasingly, 'intermediate' phenotypes for asthma and other allergic diseases have become the focus of such investigations, due to disease heterogeneity and the difficulty of defining disease status. Together with meta-analysis of existing linkage datasets and the completion of many second-stage and specialized genome scans, the recent focus in asthma and atopy genetics has been on single nucleotide polymorphism discovery and genotyping in candidate genes.


Measurements of salivary progesterone throughout the menstrual cycle in women suffering from unexplained infertility reveal high frequency of luteal phase defects.
Forty-five women suffering from unexplained infertility collected saliva for progesterone (P) measurements every morning during 1 to 3 complete cycles. A total of 27 cycles analyzed were unstimulated, 19 were stimulated by clomiphene citrate (CC), and 7 with CC, human menopausal gonadotropin (hMG), and human chorionic gonadotropin (hCG). Compared with reference profiles of salivary P from 27 normal cycles, the length and magnitude of P secretion were significantly lower in the infertility group. Luteal P concentrations were normalized during CC stimulation and significantly elevated during the CC-hMG-hCG stimulation. The other abnormalities found in the salivary P profiles of these patients included preovulatory P peaks, interruption of P secretion during luteal phase, and high P level at the beginning of menstruation. The results suggest that patients with prolonged unexplained infertility represent a heterogenous population with common luteal phase defects. The disturbance is effectively corrected with treatments stimulating gonadotropin secretion.


Five novel globin gene mutations identified in five Chinese families by next-generation sequencing.
Thalassemia is one of the most common inherited diseases worldwide. This report presents three novel cases of α-thalassemia and two novel cases of β-thalassemia caused by five different mutations in the globin gene. Next-generation sequencing (NGS) was used to identify novel α- and β-thalassemia in five individuals, which was confirmed by Sanger sequencing of the globin gene. Hematological parameters were determined by an automated cell counter, and hemoglobin electrophoresis was carried out by a capillary electrophoresis system, respectively. The isoelectric point (pI), molecular weight, and conservation for the mutations were described by the Internet software programs. The pathogenicity for globin mutations was analyzed by bioinformatics analysis and relative quantitative analysis. NGS revealed five novel cases of α- and β-thalassemia: HBA2:c.245C>T, HBA2:c.95+11_95+34delCTCCCCTGCTCCGACCCGGGCTCC, HBA2:c.54delC, HBB:c.373C>A, and HBB:c.40G>A. The clinical implications of these mutations were described. Computational predictions were made for pI, amino acid conservation, and pathogenicity of the missense mutation. Relative quantitative data of the α-globin mRNA were analyzed. Five novel globin mutations were identified in the populations of China, and those mutations were analyzed to provide a mechanistic view for their pathogenicity. These analyzed results improve genetic diagnostics for thalassemia, which can improve screening programs for thalassemia and prenatal diagnosis for Chinese population.


Tattooing and body piercing as lifestyle indicator of risk behaviors in Brazilian adolescents.
Tattooing and body piercing may be visible markers to identify adolescents whose lifestyle may put them at a higher risk for morbidity and mortality. In 664 Brazilian adolescents we found 8.4% of body modifications. Further, sexual experience, illicit drug, alcohol consumption, and anti-HBc positivity were independently associated with them. These data suggest the potential risk of tattooing/body piercing in our youths.


Successful Treatment of Multi-Drug Resistant Pseudomonas aeruginosa Bacteremia with the Recommended Renally Adjusted Ceftolozane/Tazobactam Regimen.
Ceftolozane/tazobactam (C/T) is a novel antibiotic approved for complicated intra-abdominal and urinary tract infections caused by Gram-positive and Gram-negative organisms, including some MDR strains. Little is known about the use of this agent for treatment of bacteremia and even less so about the appropriateness of the renally defined regimens. We describe a case of a 66-year-old man with a history of chronic kidney disease (baseline Cr = 3-4 mg/dl) and recurrent nephrolithiasis with bilateral stents who had positive concurrent urine and blood cultures for MDR Pseudomonas aeruginosa (PSA), susceptible only to amikacin and colistin. Due to the MDR phenotype and his underlying kidney disease, the 375 mg (250 mg/125 mg) dose of C/T was given as monotherapy every 8 h for his bloodstream infection. Once steady state was anticipated, blood was obtained at the end of infusion (1 h), and at 3, 5 and 8 h for drug concentration determination using a validated high-performance liquid chromatography method at the Center for Anti-Infective Research and Development, Hartford Hospital, Hartford. The minimum inhibitory concentration (MIC) for the PSA was 2/4 for C/T, indicating susceptibility. Concentration of ceftolozane of 21.87 µg/ml at 8 h indicated that serum concentrations were maintained above the MIC throughout the dosing interval. The patient was given 25 days of C/T and experienced a successful clinical outcome. Blood cultures obtained at 1 and 3 weeks after completion of treatment remained sterile. No adverse events were attributed to C/T. In this patient, the renally adjusted dose of C/T was safe and provided sufficiently high drug concentrations that exceeded the MIC of the infecting organism over the course of therapy. More data are required to determine the clinical utility of C/T in the setting of MDR PSA bacteremia.


Effects of overdrive stimulation on functional reentrant circuits causing ventricular tachycardia in the canine heart: mechanisms for resumption or alteration of tachycardia.
The purpose of the experiments described in this article was to investigate the effects of overdrive stimulation on functional anisotropic reentrant circuits causing ventricular tachycardia in infarcted canine ventricles. We determined how overdrive stimuli affect reentrant circuits to alter characteristics of the tachycardia. Activation patterns were determined by mapping excitation with a 192 bipolar electrode array. We found that overdrive stimuli could activate the circuits with the same pattern as the reentrant wavefront and that after overdrive stopped either the last or the next to last stimulated wavefront continued propagating through the circuit as a new reentrant impulse and tachycardia continued. When the circuit was not altered after overdrive, the exit route that the stimulated wavefront took from the circuit to activate the rest of the ventricles was also not altered and the tachycardia after overdrive had the same cycle length and QRS morphology as prior to overdrive. In some experiments, however, the overdrive stimuli did not follow the original reentrant pathway but led to the formation of a different circuit with a different exit route to the ventricles. As a result, after overdrive stimulation tachycardia had a different QRS morphology and cycle length than prior to stimulation. When the new circuit after overdrive was small and the revolution time of the reentrant impulse around the circuit was short, fibrillation occurred. Functional reentrant circuits can either be maintained or altered after a period of overdrive stimulation. The results explain many of the effects that have been seen during overdrive stimulation of clinical ventricular tachycardia.


Keynote review: Is declining innovation in the pharmaceutical industry a myth?
Increasing the rate of innovation is a requirement to achieve much-needed advances in patient care, as well as to secure the future of the pharmaceutical industry. Currently, there is a perception in the external environment that pharmaceutical R&D is no longer innovative, fails to bring new drugs to market or, at best, produces a rising number of 'me-too' drugs with no advantage over existing treatments. In addition, the cost to discover and develop new medicines (i.e. cost per launch) has risen dramatically in recent years. The quoted development cost per medicine is a reality, and is not disputed here. However, data are provided that demonstrate that with regard to innovation rates, the current perception is wrong - although there have been, and continue to be, fluctuations in drug launches, there has been a steady increase in the number of new chemical entities launched, both in absolute numbers of FDA-approved medicines and in the proportion of priority reviews.


A phenotypic change but not proliferation underlies glial responses in Alzheimer disease.
Classical immunohistochemical studies in the Alzheimer disease (AD) brain reveal prominent glial reactions, but whether this pathological feature is due primarily to cell proliferation or to a phenotypic change of existing resting cells remains controversial. We performed double-fluorescence immunohistochemical studies of astrocytes and microglia, followed by unbiased stereology-based quantitation in temporal cortex of 40 AD patients and 32 age-matched nondemented subjects. Glial fibrillary acidic protein (GFAP) and major histocompatibility complex II (MHC2) were used as markers of astrocytic and microglial activation, respectively. Aldehyde dehydrogenase 1 L1 and glutamine synthetase were used as constitutive astrocytic markers, and ionized calcium-binding adaptor molecule 1 (IBA1) as a constitutive microglial marker. As expected, AD patients had higher numbers of GFAP(+) astrocytes and MHC2(+) microglia than the nondemented subjects. However, both groups had similar numbers of total astrocytes and microglia and, in the AD group, these total numbers remained essentially constant over the clinical course of the disease. The GFAP immunoreactivity of astrocytes, but not the MHC2 immunoreactivity of microglia, increased in parallel with the duration of the clinical illness in the AD group. Cortical atrophy contributed to the perception of increased glia density. We conclude that a phenotypic change of existing glial cells, rather than a marked proliferation of glial precursors, accounts for the majority of the glial responses observed in the AD brain.


Extraoral photobiomodulation for prevention of oral and oropharyngeal mucositis in head and neck cancer patients: interim analysis of a randomized, double-blind, clinical trial.
To assess the safety and efficacy of prophylactic extraoral photobiomodulation (PBM) for the prevention of oral and oropharyngeal mucositis (OM) on clinical outcomes and survival in patients with oral cavity and oropharyngeal squamous cell carcinoma (OOPSCC). OOPSCC patients who received radiotherapy (RT) were prospectively randomized to two groups: prophylactic extraoral PBM and placebo. OM grade (NCI), pain (VAS), analgesia, and anti-inflammatory prescriptions were assessed weekly. Quality of life questionnaires (QoL) were performed at the first and last day of RT. Following RT, participants were evaluated quarterly for oncological outcomes follow-up. Fifty-five patients met the inclusion criteria. The first occurrence of OM was observed at week 1, for the placebo group (p = 0.014). Later, OM onset and severity was observed for the PBM group, with first occurrence at week 2 (p = 0.009). No difference in severe OM incidence was observed (p > 0.05). Lower mean pain score was noted at week 7 for the PBM group (2.1) compared to placebo group (4.5) (p = 0.009). Less analgesics (week 3; p = 0.009/week 7; p = 0.02) and anti-inflammatory prescription (week 5; p = 0.0346) were observed for the PBM group. Better QoL scores were observed for the PBM group at last day of RT (p = 0.0034). No difference in overall survival among groups was observed in 1 year of follow-up (p = 0.889). Prophylactic extraoral PBM can delay OM onset, reduce pain, and reduce analgesic and anti-inflammatory prescription requirements. Extraoral PBM was associated with better QoL. There was no evidence of PBM impact on oncological outcomes. TRN:RBR-4w4swx (date of registration: 01/20/2020).


The microcirculation during enflurane and isoflurane anaesthesia in dogs.
The effects of enflurane and isoflurane of 0.75 and 1.5 MAC on capillary blood flow were studied by the microsphere (9 +/- 1 microns in diameter) method in two groups of seven dogs. Simultaneously, changes in the arteriolo-venular shunt were studied by collection of venous blood at a rate of 4.8 ml.min-1 for two minutes. Enflurane anaesthesia at 0.75 MAC decreased capillary blood flow in the thyroid glands (35% of control), left and right ventricular wall (59% and 50%), adrenal gland (59%), liver (63%), spleen (56%), pancreas (35%), omentum (20%), and small intestine (60%) and at 1.5 MAC it decreased further in the thyroid glands (15%), left and right ventricular wall (31% and 32%), adrenal gland (42%), liver (47%), spleen (31%), pancreas (23%), omentum (20%), stomach (45%), and small intestine (54%). No marked changes were noted in the brain, kidney, large intestine or skeletal muscle. The arteriolo-venular shunt was decreased in the kidney from an initial rate of 12.1 to 3.8% at 0.75 MAC and to 2.5% at 1.5 MAC enflurane. In contrast, during isoflurane anaesthesia, capillary blood flow remained unchanged, except for a decrease to the thyroid glands (43%) and right ventricular wall (74%) during 1.5 MAC anaesthesia. However, the arteriolo-venular shunt was increased in the brain from 12.0 to 29.7% and 33.0% during 0.75 and 1.5 MAC isoflurane anaesthesia, respectively. It also increased from 25.0 to 41.0% and 46.3% in the skeletal muscle, and from 8.9 to 19.9% and 17.4% in the whole systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)


Exploring the association between Cerebral small-vessel diseases and motor symptoms in Parkinson's disease.
to explore the association between cerebral small-vessel diseases (CSVDs) and motor symptoms in Parkinson's disease (PD). 137 PD patients were recruited into the study. Detailed motor symptoms, including tremor, rigidity, bradykinesia, and axial impairment, were evaluated using Unified Parkinson's disease Rating Scale (UPDRS). Non-motor symptoms, including cognition, anxiety, and depression, were evaluated using Montreal Cognitive Assessment (MoCA), Hamilton anxiety scale (HAMA), and Hamilton depression scale (HAMD). Brain MRI was used to assess the subtypes of CSVDs, including lacunes, enlarged perivascular spaces (EPVS), and white matter hyperintensities (WMH). WMH were furtherly divided into deep WMH (DWMH) and periventricular hyperintensities (PVH). The association between CSVDs and motor symptoms was analyzed. Patients were divided into the postural instability and gait disability (PIGD) group and non-PIGD group. Demographic, clinical and CSVDs variables were compared between the two groups. CSVDs subtypes were all detected in the participants with different prevalence rates and severity degrees. We found a close association between EPVS in basal ganglia and the tremor score (p = 0.032), and between DWMH in the frontal and occipital lobes and the axial motor score (p < 0.05) through the spearman and multivariate liner regression analysis. Compared with the non-PIGD group, the PIGD group demonstrated more serious cognitive impairment and DWMH in the frontal and occipital lobes (p < 0.05). The demographic characteristics and vascular risk factors of the PIGD group were not different from those of the non-PIGD group. Cognitive impairment and DWMH in the frontal lobe were identified to be independent risk factors of PIGD motor phenotype. We identified a close association between the CSVDs and motor symptoms in PD and DWMH in the frontal lobe was a risk factor of PIGD motor phenotype, which supports the contribution of vascular pathology in PD.


Identification of the +1 ribosomal frameshifting site of LRV1-4 by mutational analysis.
Leishmania virus (LRV)1-4 has been reported to produce a fusion of ORF2 and ORF3 via a programmed +1 frameshift in the region where ORF2 and ORF3 overlap (Lee et al., 1996). However, the exact frameshift site has not been identified. In this study, we compared the frameshift efficiency of a 259bp (nt. 2565-2823), frameshift region of LRV1-4, and the 71bp (nt. 2605-2678) sub-region where ORF2 and ORF3 overlap. We then predicted the frameshift site using a new computer program (Pseudoviewer), and finally identified the specific region associated with the mechanism of the LRV1-4's +1 frameshift by means of a mutational analysis based on the predicted structure of LRV1-4 RNA. The predicted structure was confirmed by biochemical analysis. In order to measure the frameshift efficiency, constructs that generate luciferase without a frameshift or with a +1 frameshift, were generated and in vitro transcription/translation analysis was performed. Measurements of the luciferase activity generated, showed that the frameshift efficiency was about 1% for both the 259bp (LRV1-4 259FS) and 71bp region (LRV1-4 71FS). Luciferase activity was strongly reduced in a mutant (LRV1-4 NH: nt. 2635-2670) with the entire hairpin deleted and in a mutant (LRV1-4 NUS: nt. 2644-2659) with the upper stem of the hairpin deleted. These results indicate that the frameshift site in LRV1-4's is in the 71bp region where ORF2 and ORF3 overlap, and that nt. 2644-2659 (the upward hairpin stem) play a key role in generating the +1 frameshift.


Role of antioxidants and trace elements in health and immunity of transition dairy cows.
A number of antioxidants and trace minerals have important roles in immune function and may affect health in transition dairy cows. Vitamin E and beta-carotene are important cellular antioxidants. Selenium (Se) is involved in the antioxidant system via its role in the enzyme glutathione peroxidase. Inadequate dietary vitamin E or Se decreases neutrophil function during the perpariturient period. Supplementation of vitamin E and/or Se has reduced the incidence of mastitis and retained placenta, and reduced duration of clinical symptoms of mastitis in some experiments. Research has indicated that beta-carotene supplementation may enhance immunity and reduce the incidence of retained placenta and metritis in dairy cows. Marginal copper deficiency resulted in reduced neutrophil killing and decreased interferon production by mononuclear cells. Copper supplementation of a diet marginal in copper reduced the peak clinical response during experimental Escherichia coli mastitis. Limited research indicated that chromium supplementation during the transition period may increase immunity and reduce the incidence of retained placenta.


Screening for heart transplantation and left ventricular assist system: results from the ScrEEning for advanced Heart Failure treatment (SEE-HF) study.
Heart transplantation (HTx) and implantable left ventricular assist systems (LVAS) improve outcomes in advanced heart failure but may be underutilized. We hypothesized that screening can identify appropriate candidates. The ScrEEning for advanced Heart Failure treatment (SEE-HF) study was a multicentre prospective study screening patients with existing cardiac resynchronization therapy (CRT) and/or implantable cardioverter-defibrillator (ICD) for ejection fraction ≤40% and New York Heart Association (NYHA) class III-IV, and subsequently for guideline-based HTx and LVAS indication. Of 1722 (mean age 64 ± 14 years, 26% women) patients screened at eight centres in seven European countries, 121 (7.0%) were eligible and 99 (5.7%; mean age 61 ± 10 years, 19% women) patients were enrolled for detailed assessment. Twenty-six of the 99 enrolled patients (26%) were eligible for either HTx or LVAD (18 eligible for HTx; 7 eligible for LVAD; and 1 eligible for both). Eleven patients were listed for HTx and three received an LVAS. Eligible patients were 61 ± 8 years and 19% women, whereas those actually receiving intervention were 56 ± 8 years and 8% women. Among patients with CRT and/or ICD, a minority have NYHA class III-IV heart failure and ejection fraction ≤40%. Among these, however, more than one-quarter have an unrecognized need for HTx or LVAS. When patients are offered intervention based on screening, many decline. Discrepancies exist between clinical and patient equipoise. Clinical Trial Registration ClinicalTrials.gov Unique Identifier: NCT00894387.


Ductal lavage findings in women with mammographic microcalcifications undergoing biopsy.
We designed a prospective study to assess the likelihood that early lesions presenting as mammographic calcifications could be accessed for cytological diagnosis by ductal lavage (DL). Consenting women with calcifications (Breast Imaging Reporting and Data System 4 or 5) underwent DL of fluid-yielding ducts (FYDs) before stereotactic core or excisional biopsy. The DL catheter was used to inject .2 to 1 mL of Isovue 300 into the duct to determine whether the FYD corresponded to the duct containing calcifications (designated overlap). Additional FYDs were injected, if possible, until overlap was identified. DL cytology was compared with histology. Twenty women were enrolled (mean age, 54.2 years); the mean size of the calcification-bearing area was 190 mm(2). The histological findings were as follows: 1 invasive cancer, 9 ductal carcinomas-in-situ (DCIS), 5 atypical hyperplasias, and 5 usual hyperplasias or fibrocystic changes. Four women had no FYD. In 15 women who underwent DL and ductography, overlap of dye and calcifications was seen in 4 (27%): 1 fibrocystic change, 1 hyperplasia, 1 atypical hyperplasia (cytological diagnosis mildly atypical), and 1 DCIS (cytological diagnosis benign). Of the remaining 8 DCIS lesions, 4 had no nipple aspiration fluid, 1 showed extravasation, and 3 were lavaged but the duct did not overlap. These results are consistent with data from women undergoing mastectomy for larger invasive cancer and DCIS and show that cancer-containing ducts do not yield nipple fluid in most cases.


Transforming single-band static FSS to dual-band dynamic FSS using origami.
Frequency selective surfaces (FSSs) have been used to control and shape electromagnetic waves. Previous design approaches use complex geometries that are challenging to implement. With the purpose to transform electromagnetic waves, we morph the shapes of FSS designs based on origami patterns to attain new degrees of freedom and achieve enhanced electromagnetic performance. Specifically, using origami patterns with strongly coupled electromagnetic resonators, we transform a single-band FSS to a dual-band FSS. We explain this transformation by showing that both symmetric and anti-symmetric modes are excited due to the strong coupling and suitable orientation of the elements. Also, our origami FSS can fold/unfold thereby tuning (i.e., reconfiguring) its dual-band performance. Therefore, the proposed FSS is a dynamic reconfigurable electromagnetic structure whereas traditional FSSs are static and cannot change their performance.


Ubc9-mediated sumoylation leads to transcriptional repression of IRF-1.
To characterize the regulatory mechanism of the interferon regulatory factor (IRF) family, we performed yeast two-hybrid screening with IRF-2 and isolated the small ubiquitin-related modifier (SUMO)-conjugating enzyme Ubc9, which also interacts with other IRF family members IRF-1 and ICSBP. Subsequent assays indicated that among the IRF family members, only IRF-1 interacts with SUMO-1 through its transcriptional activation domain. The interaction between IRF-1 and SUMO-1 was confirmed in vitro by GST pull-down assays and in vivo by co-localization assays. Furthermore, this interaction led to the Ubc9-mediated sumoylation of IRF-1 in vitro and in vivo. Transient transfection assays revealed that Ubc9 or SUMO inhibits the transcriptional activity of IRF-1 in a dose-dependent manner. Finally, Ubc9 and SUMO cooperate in the transcriptional repression of IRF-1. Taken together, these observations suggest that Ubc9 functions as a transcriptional repressor of IRF-1 by inducing sumoylation, and that this effect may be required for the physiological activity of IRF-1.


Life Threatening haemoptysis in primary lung cancer-signet ring cell carcinoma.
Primary signet ring cell carcinoma of the lung is a rare non-small cell carcinoma of the lung with extremely aggressive features and poor prognosis. The diagnosis mainly required tissue biopsy with immunohistochemical analysis and gene mutation studies. We describe a unique case of primary signet ring cell carcinoma of the lung presenting with life threatening haemoptysis along with literature review of prognosis and management of this rare clinical entity.


Comparison of cytohistologic techniques in diagnosis of gastroesophageal malignancy.
To evaluate the diagnostic performance of various endoscopic cytologic techniques, namely, brushing cytology, touch smear cytology and crush cytology, and comparison with concurrent biopsy results in diagnosis of gastroesophageal malignancy. This prospective study was conducted on 100 patients, with 78 clinically suspected cases of esophageal malignancy and 22 cases of gastric malignancy. The diagnostic accuracy of touch smear in esophageal malignancy was significantly higher (94.12%) than brushing and crush smears (89.71% each), and endoscopic biopsy had the diagnostic accuracy of 88.24%. The diagnostic accuracy of combined brushing and biopsy was 100%; it was 97.06% for touch smears combined with biopsy. In comparison, the diagnostic accuracy in gastric malignancy was 75% for brushing alone, which was significantly lower than touch smear (87.5%) and endoscopic biopsy (87.5%). The diagnostic yield for crush smear was 81.25%. A combination of touch smears and biopsy had a diagnostic yield of 100%; it was 93.75% for combined brushings and biopsy. A combination of cytohistologic techniques resulted in a statistically significant increase in the diagnostic yield of gastroesophageal malignancies and thus cytologic techniques may act as adjunct to biopsy histology to increase the diagnostic efficiency.


Expression analysis of the heat shock protein genes and cellular reaction in dojo loach (Misgurnus anguillicaudatus) under the different pathogenic invasion.
As molecular chaperones, heat shock proteins (HSPs) play essential roles in cells in response to stress conditions. Recent studies about immune functions of HSPs in fish have also been reported. In this study, based on the reported cDNA sequences of the four HSP genes, HSP70, HSC70, HSP90α and HSP90β, the temporal expression patterns of the four genes during embryonic development of dojo loach(Misgurnus anguillicaudatus) was assayed with qRT-PCR. All of the four genes were ubiquitously expressed in all detected embryonic developmental stages. Among of them, HSP70, HSC70 and HSP90β were highly expressed in the organ formation stage, while HSP90α was the highest expressed in myotome formation stage. Further, the immune responses of the four HSP genes were assayed when loach were infected with three different pathogens, bacterium (Flavobacterium cloumnare G4), parasite (Ichthyophthirius multifiliis) and fungus (Saprolegnia). All of the four genes were differentially expressed in four tissues such as skin, gills, spleen and kidney in response to the pathogenic invasion, but both HSP70 and HSP90α expressions were dramatically up-regulated. Further, the cellular responses of the loach skinand gill tissues were observed, in which the number of the skin goblet cells were significantly increased, and the gill lamellae became shorter and wider after infected. Thus, our work indicated that the HSPs may directly or indirectly involved in immune defense in fish, at least in the loach.


Impact of prenatal amoxicillin exposure on hippocampal development deficiency.
Amoxicillin has been widely used to treat infectious diseases during pregnancy. Current studies suggest that amoxicillin exposure during pregnancy could lead to developmental disorders in the offspring and increase the incidence of long-term complications such as asthma and kidney damage in adulthood. However, the adverse effects of prenatal amoxicillin exposure (PAmE) including administration stage, doses and courses on fetal hippocampal neurodevelopment and its function in the offspring have not been elucidated. In this study, we intend to investigate the effects of PAmE on fetal hippocampal development and its possible mechanisms. Pregnant Kunming mice were given intragastric administration with amoxicillin at different administration stage, doses and courses, and GD (gestational day) 18 offspring hippocampus was collected for morphological and development-related functional assays, and the molecular mechanisms were explored. PAmE induced hippocampal hypoplasia in the offspring with suppressed hippocampal neuronal cell proliferation and impaired neuronal synaptic plasticity comparatively; hippocampal astrocyte and microglia were damaged to varying degrees. The developmental toxicity of PAmE in fetal mices varies by time, dose, and course of treatment. The most severe damage was observed in the late gestation, high dose, and multi-course dosing groups. The significant reduction either in SOX2, an essential gene in regulating neural progenitor cell proliferation, and reduction of genes related to the Wnt/β-catenin pathway may suggest that the key role of SOX2/Wnt/β-catenin pathway in impaired hippocampal development in the offspring due to PAmE. In this study, PAmE was found to be developmentally toxic to the hippocampus thus to induce developmental damage to various hippocampal cells; Even with current clinically safe doses, potential hippocampal damage to offspring may still present; This study provides a theoretical and experimental basis for guiding the rational usage of drugs during pregnancy and giving effectively assessment of the risk on fetal hippocampal developmental toxicity.


Nuclear translocation of telomerase reverse transcriptase and calcium signaling in repression of telomerase activity in human lung cancer cells by fungal immunomodulatory protein from Ganoderma tsugae.
Recombinant fungal immunomodulatory protein, reFIP-gts, was cloned from Ganoderma tsugae and purified. In our previous study, it was shown that reFIP-gts has anti-telomerase effects in A549 cells. Here, we proved that reFIP-gts entry into the cell and localization in endoplasmic reticulum can result in ER stress, thereby increasing ER stress markers (CHOP/GADD153) and intracellular calcium release in A549 cells. The use of calcium chelator restores reFIP-gts-mediated reduction in telomerase activity. These results strongly suggest that ER stress induces intracellular calcium release and results in inhibition of telomerase activity. Although reFIP-gts decreased hTERT mRNA level in both A549 and H1299 cells, only the telomerase activity in A549 cells was inhibited. Surprisingly, we found that reFIP-gts induces translocation of hTERT from the nucleus into the cytosol in A549 cells but not in H1299 cells. Using leptomycin B, nuclear export inhibitor, we showed that hTERT is not transported. Using MG132, a proteasome inhibitor, reFIP-gts also prevents hTERT translocation from proteasome degradation. Taken together, these results indicate that reFIP-gts inhibits telomerase activity in lung cancer cells through nuclear export mechanisms, which might be mediated by ER stress-induced intracellular calcium level.


PROKR2 Mutations in Patients with Short Stature Who Have Isolated Growth Hormone Deficiency and Multiple Pituitary Hormone Deficiency
Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of pituitary hormone deficiencies, suggesting a potential role for the PROK2 pathway in pituitary development, in addition to its role in gonadotropin releasing hormone-expressing neuron development. Here, we present the clinical and molecular findings of four patients with PROKR2 mutations. Next-generation targeted sequencing was used to screen 25 genes in 59 unrelated patients with multiple pituitary hormone deficiency (MPHD), isolated growth hormone (GH) deficiency, or idiopathic short stature. Two different, very rare PROKR2 missense alterations classified as pathogenic (NM_144773.4:c.518T>G; NP_658986.1:p. (Leu173Arg)) and likely pathogenic (NM_144773.4:c.254G>A; NP_658986.1:p.(Arg85His)) were identified in four patients in heterozygous form. Patient 1 and Patient 2 presented with short stature and were diagnosed as GH deficiency. Patient 3 and Patient 4 presented with central hypothyroidism and cryptorchidism and were diagnosed as MPHD. No other pathogenic alterations were detected in the remaining 24 genes related to short stature, MPHD, and hypogonadotropic hypogonadism. Segregation analysis revealed asymptomatic or mildly affected carriers in the families. PROKR2 dominance should be kept in mind as a very rare cause of GH deficiency and MPHD. Expressional variation or lack of penetrance may imply oligogenic inheritance or other environmental modifiers in individuals who are heterozygous carriers.