A high-density collection of EMS-induced mutations for TILLING in Landsberg erecta genetic background of Arabidopsis.
Arabidopsis thaliana is the main model species for plant molecular genetics studies and world-wide efforts are devoted to identify the function of all its genes. To this end, reverse genetics by TILLING (Targeting Induced Local Lesions IN Genomes) in a permanent collection of chemically induced mutants is providing a unique resource in Columbia genetic background. In this work, we aim to extend TILLING resources available in A. thaliana by developing a new population of ethyl methanesulphonate (EMS) induced mutants in the second commonest reference strain. In addition, we pursue to saturate the number of EMS induced mutations that can be tolerated by viable and fertile plants. By mutagenizing with different EMS concentrations we have developed a permanent collection of 3712 M2/M3 independent mutant lines in the reference strain Landsberg erecta (Ler) of A. thaliana. This population has been named as the Arabidopsis TILLer collection. The frequency of mutations per line was maximized by using M1 plants with low but sufficient seed fertility. Application of TILLING to search for mutants in 14 genes identified 21 to 46 mutations per gene, which correspond to a total of 450 mutations. Missense mutations were found for all genes while truncations were selected for all except one. We estimated that, on average, these lines carry one mutation every 89 kb, Ler population providing a total of more than five million induced mutations. It is estimated that TILLer collection shows a two to three fold higher EMS mutation density per individual than previously reported A. thaliana population. Analysis of TILLer collection demonstrates its usefulness for large scale TILLING reverse genetics in another reference genetic background of A. thaliana. Comparisons with TILLING populations in other organisms indicate that this new A. thaliana collection carries the highest chemically induced mutation density per individual known in diploid species.


India: population: birth curbs fail.
Government efforts at curbing population growth has been a failure, reports quoting Health Minister Baburao Shankaranand said. He blamed the government of former Prime Minister Morarji Desai (1977-79) for the inability to reduce the birth rate. The minister, a father of 8, was further reported to have pointed to the 1971 census results as reflecting the failure. The enumeration placed the total Indian population at 684 million which was 12 million more than projected. He said the government of Prime Minister Indira Gandhi has adopted measures to reduce the birth rate from the current 36/1,000 population to 21 by the end of the present century. "We will stick to persuasion, motivation and education" but will not use force, he added.


The association between lactate and muscle aerobic substrate oxidation: Is lactate an early marker for metabolic disease in healthy subjects?
Fasting plasma lactate concentrations are elevated in individuals with metabolic disease. The aim of this study was to determine if the variance in fasting lactate concentrations were associated with factors linked with cardiometabolic health even in a young, lean cohort. Young (age 22 ± 0.5; N = 30) lean (BMI (22.4 ± 0.4 kg/m2 ) women were assessed for waist-to-hip ratio, aerobic capacity (VO2 peak), skeletal muscle oxidative capacity (near infrared spectroscopy; fat oxidation from muscle biopsies), and fasting glucose and insulin (HOMA-IR). Subjects had a mean fasting lactate of 0.9 ± 0.1 mmol/L. The rate of deoxygenation of hemoglobin/myoglobin (R2 = .23, p = .03) in resting muscle and skeletal muscle homogenate fatty acid oxidation (R2 = .72, p = .004) were inversely associated with fasting lactate. Likewise, cardiorespiratory fitness (time to exhaustion during the VO2 peak test) was inversely associated with lactate (R2 = .20, p = .05). Lactate concentration was inversely correlated with HDL:LDL (R2 = .57, p = .02) and positively correlated with the waist to hip ratio (R2 = .52, p = .02). Plasma lactate was associated with various indices of cardiometabolic health. Thus, early determination of fasting lactate concentration could become a common biomarker used for identifying individuals at early risk for metabolic diseases.


[Prevention and management of anterior resection syndrome].
Because of the improvement of surgical technique and the widely use of multimodality therapy, more patients with rectal cancer undergo sphincter-preserving surgery. However, it has been reported that up to 90% of such patients will suffer from bowel dysfunction, ranging from increased bowel frequency to faecal incontinence or evacuatory dysfunction. This wide spectrum of symptoms after resection of the rectum has been termed anterior resection syndrome (ARS). This disordered bowel function has a substantial negative effect on quality of life, however, the causal mechanisms have not been clarified. The present review discusses the clinical manifestation, underlying mechanisms, as well as prevention and treatment strategies.


Digital processing of dual-plate speckle photography data.
Dual-plate speckle photography provides a technique for canceling rigid body displacements of an object by recording the images that correspond to the two deformation states on separate photographic plates. When both plates are positioned with a glass base between the emulsions and illuminated by a laser beam, a pattern of circular fringes is formed. Speckle displacement can be determined by measuring the distance between the fringe pattern center and the undiffracted laser beam. The performance of an algorithm for automatic analysis of these fringes is evaluated by using computer-generated fringe patterns. Accuracy is determined for different values of speckle displacements and fringe visibilities.


Pharmacokinetics of intravenous mycophenolate mofetil after allogeneic blood stem cell transplantation.
Mycophenolate mofetil (MMF) has shown synergistic effects in combination with cyclosporin A (CsA) in prevention of acute graft versus host disease (GvHD) after allogeneic blood stem cell transplantation (BSCT) in preclinical animal models. After having measured low plasma levels of the active metabolite mycophenolic acid (MPA) in recipients of allogeneic blood stem cell transplants after oral administration of MMF, we initiated a phase I/II study evaluating different dose levels of the intravenous (i.v.) formulation together with standard dose CsA. A total of 15 patients received i.v. MMF in two split doses for 21 d after allogeneic BSCT from related (n=9) and unrelated (n=6) donors. Total daily doses of 25, 28, 31 and 34 mg/kg were investigated in 3-5 patients at each dose level. Plasma concentrations of MPA and its metabolite mycophenolic acid glucuronide (MPAG) were measured by high-performance liquid chromatography (HPLC). Mean trough blood levels of MPA ranged between 68.8 and 340 ng/mL with a median of 146.7 ng/mL. The mean MPA AUC0-12 h after first dose ranged between 19349+/-5087 ng * h/mL and 25705+/-3042 ng * h/mL and correlated with the dose level of MMF. The incidence of acute GvHD>grade I was 40%. No dose limiting toxicities were observed. The application of i.v. MMF is safe at a weight-adjusted dose between 25 and 34 mg/kg after allogeneic BSCT. The measured trough blood levels of MPA in patients after BSCT were ten times lower than in healthy volunteers. The toxicity induced by the conditioning therapy seems to negatively influence the pharmacokinetic behavior of MMF, MPA and MPAG.


Adverse effects of suxamethonium. Failure of prevention by atracurium or fazadinium.
One hundred patients were allocated randomly to pretreatment with atracurium 2.5 mg, atracurium 5 mg, fazadinium 3.75 mg or saline 3 minutes before the injection of suxamethonium. The effect upon neuromuscular conduction was studied by recording the mechanical response of the adductor pollicis muscle to indirect stimulation of the ulnar nerve using repeated 2 Hz train of four stimuli. Blood samples were taken at intervals for the measurement of serum potassium. There was no significant difference in the incidence of postoperative muscle pains between the groups in the first 72 hours following anaesthesia. The use of the larger pretreatment dose of atracurium resulted in clinically significant neuromuscular blockade in three of the subjects. Minimal changes in serum potassium occurred in all patients but there was no statistical difference between the groups.


Migration of silver from nanosilver-polyethylene composite packaging into food simulants.
An analytical method for the determination of silver in food simulants (3% (w/v) aqueous acetic acid or 95% (v/v) aqueous ethanol) was developed based on inductively coupled plasma mass spectrometry (ICP-MS). Recoveries ranged from 87% to 109% and RSDs ranged from 0.7% to 7.8%. The procedure was applied to determine the migration of silver from nanosilver-polyethylene food packaging film into food simulants at different temperatures and migration times. Results indicated that the maximum migration ratios were 1.70%, 3.00% and 5.60% for 3% (w/v) aqueous acetic acid at 20, 40 and 70 °C, respectively, while for 95% (v/v) aqueous ethanol the maximum migration ratios were 0.24%, 0.23% and 0.22% at 20, 40 and 70 °C.


Mesalazine for the Treatment of Symptomatic Uncomplicated Diverticular Disease of the Colon and for Primary Prevention of Diverticulitis: A Systematic Review of Randomized Clinical Trials.
Symptomatic uncomplicated diverticular disease (SUDD) is a common gastrointestinal disease, because it affects about one fourth of the patient harboring colonic diverticula. To assess the effectiveness of mesalazine in improving symptoms (namely abdominal pain) and in preventing diverticulitis occurrence in patients with SUDD. Only randomized clinical trials (irrespective of language, blinding, or publication status) that compared mesalazine with placebo or any other therapy in SUDD were evaluated. The selected endpoints were symptom relief and diverticulitis occurrence at maximal follow-up. Absolute risk reduction (ARR, with 95% confidence interval) and the number needed to treat were used as measures of the therapeutic effect. Six randomized clinical trials enrolled 1021 patients: 526 patients were treated with mesalazine and 495 with placebo or other therapies. Symptom relief with mesalazine was always larger than that with placebo and other therapies. However, absolute risk reduction was significant only when mesalazine was compared with placebo, a high-fiber diet, and low-dose rifaximin. The incidence of diverticulitis with mesalazine was lower than that observed with placebo and other treatments, being significant only when compared with placebo. Mesalazine is effective in achieving symptom relief and primary prevention of diverticulitis in patients with SUDD.


Imaging brain function in humans at 7 Tesla.
This article describes experimental studies performed to demonstrate the feasibility of BOLD fMRI using echo-planar imaging (EPI) at 7 T and to characterize the BOLD response in humans at this ultrahigh magnetic field. Visual stimulation studies were performed in normal subjects using high-resolution multishot EPI sequences. Changes in R(*)(2) arising from visual stimulation were experimentally determined using fMRI measurements obtained at multiple echo times. The results obtained at 7 T were compared to those at 4 T. Experimental data indicate that fMRI can be reliably performed at 7 T and that at this field strength both the sensitivity and spatial specificity of the BOLD response are increased. This study suggests that ultrahigh field MR systems are advantageous for functional mapping in humans. Magn Reson Med 45:588-594, 2001.


Clinicopathological Features of Intraductal Pancreatic Neuroendocrine Tumors.
Objective To evaluate the clinical and pathologic characteristics of intraductal pancreatic neuroendocrine tumors (PanNETs). Methods Four cases of intraductal PanNETs were studied by light microscopy and immunohistochemistry with the analysis of morphologic features and review of relevant literatures. Results Two female patients and two male patients aged 41- 58 years were enrolled in this study. The chief complaint was abdominal pain in two patients,vomiting in one patient,and jaundice in the last patient. Imaging examination showed intraductal neoplasm with diagnosis as intraductal papillary mucinous neoplasm (IPMN) in case 1; space-occupying lesions were found in the head of pancreas in the other three cases with pancreatic ductal ectasia and distal pancreatic atrophy. Grossly the masses were located in pancreatic main duct and invaded into surrounding pancreatic parachyma. Microscopically the tumors arranged with solid pattern,with some trabecular structures in the last two cases. Small duct and ductules were seen in intraductal PanNETs. The immunohistochemical expression showed that SYN and CgA were positive in neoplastic cells and negative in small duct and ductules.Conclusions Intraductal PanNETs are rare conditions. The clinical symptoms and imaging findings are similar to IPMN or pancreatic carcinoma. The tumors are located within pancreatic duct partly and can invade the pancreatic parenchyma. Microscopically the neuroendocrine tumors mix with small duct and forms ductulo-insular structure,which should be differentiated with mixed ductal endocrine carcinoma. The grade and prognosis are similar to those of classical neuroendocrine tumors.


Hematology and plasma chemistry reference intervals for mature laboratory pine voles (Microtus pinetorum) as determined by using the nonparametric rank percentile method.
Plasma biochemical and hematologic values are important parameters for assessing animal health and experimental results. Although normal reference values for many rodent species have been published, there is a dearth of similar information for the genus Microtus. In addition, most studies use a mean and standard deviation to establish reference intervals, but doing so is not the recommendation of the Clinical and Laboratory Standards Institute (formerly the National Committee on Clinical Laboratory Standards) or the International Federation of Clinical Chemistry and Laboratory Medicine. The purpose of this study was to establish normal reference parameters for plasma biochemistry and hematology in mature pine voles (Microtus pinetorum) by using the nonparametric rank percentile method as recommended by the 2 laboratory medicine organizations mentioned. Samples of cardiac blood from a closed colony of pine voles were collected at euthanasia and evaluated under rodent settings on 2 automated hematology analyzers from 2 different manufacturers and on the same type of automated biochemistry analyzer. There were no sex-associated clinically significant differences between the sexes; younger animals had a lower hematocrit, higher mean corpuscular volume, and lower mean corpuscular hemoglobin concentration than did older animals. Only platelet counts differed when comparing hematologic values from different analyzers. Relative to rats and mice, pine voles have a lower mean corpuscular volume and higher red blood cell count, higher blood urea nitrogen, much higher alanine aminotransferase, and lower glucose and phosphorous concentrations. Hematology and plasma biochemical results obtained in this study are considered representative for healthy adult laboratory pine voles under similar environmental conditions.


Large radiopaque lesion in the posterior mandible: A challenging case.
Radiopaque lesions of the jawbones are frequently encountered in dental radiographs. A variety of conditions such as chronic inflammation, soft tissue calcifications, fibrosseous lesions, odontogenic tumors, and bone neoplasms can manifest as radiopaque lesions on the jawbones. These radiopaque lesions are often difficult to distinguish from each other, hence making the formulation of differential diagnosis challenging. A thorough patient's history and clinical examination supplemented by appropriate investigations will enable the clinician in narrowing down the differential diagnosis and to identify the condition accurately. Presented here is a case of the large radiopaque lesion on posterior mandible surrounded by lytic areas in a 20-year-old male patient.


Testis conservation studies in germ cell cancer justified by improved primary chemotherapy response and reduced delay, 1978-1994.
To investigate the need for the continued encouragement of early diagnosis of germ cell cancer of the testis, in view of the prevailing cure rate of 95%. The study comprised a retrospective review of 453 unselected and previously untreated patients referred to one centre between 1978 and 1984, comparing the delay from first symptoms with the histological diagnosis. With a delay of < 30 days, 20% of patients had overt metastases at presentation and if the delay was > 4 months. 55% had metastases (chi-squared trend = 15.9, P < 0.001); 18% of Stage-1 patients under surveillance with a delay of < 30 days relapsed, compared with 38% of those with a delay of > 4 months. During the period 1978-1983, 16% of patients were seen after a delay of < 60 days, during the period 1984-1988 the proportion was 22% and during 1989-1994, 31% (chi-squared trend = 8.2, P < 0.004). There was a non-significant trend for a more prolonged delay in those aged < 21 years and > 40 years. Thirty-two patients had chemotherapy with the primary tumour in situ; at orchidectomy, 13 of 18 had no viable malignancy and four of five with viable malignancy also had drug-resistant metastases. Fourteen did not undergo orchidectomy; within a median follow-up of 9 years, one developed a second (histologically different) tumour after 12 years. The outcome of preliminary attempts to use neoadjuvant chemotherapy with or without partial orchidectomy for patients with tumours in a solitary testis is discussed. These findings clearly justify the continued encouragement of early diagnosis, possibly best performed as part of an extended educational programme of genital health at puberty. The long-term potential for testis conservation should be explored initially in tumours in a solitary testis.


RNA epigenetic modification: N6-methyladenosine.
N(6)-methyladenosine (m(6)A) is one of the most prevalent internal modifications in eukaryotic messenger RNA. The dynamic and reversible modification is installed by methyltransferase complex charactered three subunits: METTL3 (Methyltransferase-like protein 3), METTL14 (Methyltransferase-like protein 14) and WTAP (Wilms tumor 1-associating protein), and erased by two independent demethylases, FTO (Fat mass and obesity associated protein) and ALKBH5 (AlkB homolog 5), in an α-ketoglutarate (α-KG)- and Fe(II)-dependent manner. m(6)A plays funtions in controlling RNA metabolism through the recognition by m(6)A reader proteins, the YTH domain family proteins and HNRNPA2B1 (Heterogeneous nuclear ribonucleoproteins A2B1) . In this review, we summarized distributive features and vital roles of m(6)A and its associated proteins in RNA metabolisms and biological significance, which will help us better understand this new exciting emerging epitranscriptome research field.


Engineered reversal of drug resistance in cancer cells--metastases suppressor factors as change agents.
Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic intervention remains a pressing clinical need. To identify factors that impact drug resistance herein we built a model that couples inherent cell-based response toward drugs with transcriptomes of resistant/sensitive cells. To test this model, we focused on a group of genes called metastasis suppressor genes (MSGs) that influence aggressiveness and metastatic potential of cancers. Interestingly, modeling of 84 000 drug response transcriptome combinations predicted multiple MSGs to be associated with resistance of different cell types and drugs. As a case study, on inducing MSG levels in a drug resistant breast cancer line resistance to anticancer drugs caerulomycin, camptothecin and topotecan decreased by more than 50-60%, in both culture conditions and also in tumors generated in mice, in contrast to control un-induced cells. To our knowledge, this is the first demonstration of engineered reversal of drug resistance in cancer cells based on a model that exploits inherent cellular response profiles.


Comparison of the Nonlinear Dynamic Pre- and Post-LED Equalization.
Visible Light Communications (VLC) have gained much popularity lately. In such a system, a white LED (Light-Emitting Diode) plays a double role as a light source and a transmitter. The main problem here is that the LED exhibits a low bandwidth and high nonlinearity, so the equalization of the LED nonlinear dynamic response is necessary. For this, various equalizers are used. This paper compares the pre- and post-equalizer performance in terms of the received signal quality for a channel that includes a nonlinear element of limited bandwidth, such as an LED. Multilevel Pulse Amplitude Modulation (PAM) was selected as the signal format, as well as a variant of the Volterra series equalizer as the compensating element. The results obtained may be used for the correction of the dynamic characteristics of LEDs applied in VLC systems. For the sake of comparison, we used Modulation Error Ratio (MER) values at the receiver output. The dynamic nonlinear behavior was modeled by a Wiener-Hammerstein device, whereas the post/pre-equalizer was based on the dynamic deviation reduction-based Volterra series. The obtained results indicate that the post- and pre-equalizer performed comparably for the linear/moderately nonlinear channels and for a high noise level. In the case of high nonlinearity and a large SNR (Signal-to-Noise Ratio) values, the post-equalizer performed somewhat better in terms of MER by a few dB at maximum.


Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E.
Oral administration of autoantigens suppresses development of autoimmunity in several animal models, and is being tested in clinical trials in patients with autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent diabetes mellitus at 15 to 20 weeks of age, after mononuclear cell (MNC) infiltration of the pancreatic islets of Langerhans and destruction of insulin-producing beta cells. We have previously shown that oral administration of insulin suppresses insulitis and development of diabetes in the NOD mouse. Oral insulin has no metabolic effect on blood glucose. Oral insulin mediates its effect through a T cell-dependent mechanism as shown by adoptive transfer and T cell depletion experiments, but the mechanisms responsible have not been fully explored. We now report a serial analysis of the cells and cytokines associated with development of diabetes in NOD mice, and contrast this with the findings in animals fed equine insulin or a control protein (ovalbumin). Animals were fed 1 mg twice a week for 5 weeks, beginning at 5 weeks of age. Marked insulitis in naive or ovalbumin-fed NOD mice occurred at 10 weeks, at which time a dense peri-islet and intra-islet MNC infiltration was observed. Immunohistological studies using monoclonal antibodies showed that infiltrating MNC consisted mainly of CD4+ T cells ( > 75% of leukocytes) plus smaller numbers of macrophages and CD8+ T cells. These cells displayed evidence of immune activation with expression of receptors for interleukin-2 (IL-2R) plus Th1 cytokines; dense labeling for IFN-gamma and tumor necrosis factor-alpha, plus lesser amounts of IL-2, was observed. MNC lacked labeling for IL-4, IL-10, prostaglandin-E, or transforming growth factor-beta. By contrast, at 10 weeks, pancreatic tissues from NOD mice fed insulin showed considerably less insulitis, and the residual MNC, although still largely CD4+ T cells plus macrophages, showed dense labeling for IL-4, IL-10, prostaglandin-E, and transforming growth factor-beta and an absence of IL-2, IFN-gamma or tumor necrosis factor-alpha Taken together with our previous findings, these data indicate that oral administration of insulin affects the development of diabetes in NOD mice through the generation of cells that elaborate immunoregulatory cytokines within the target organ and shift the balance from a Th1 to a Th2 pattern of cytokine expression.


Multi-Omics Association Reveals the Effects of Intestinal Microbiome-Host Interactions on Fat Deposition in Broilers.
Growing evidence indicates that gut microbiota factors cannot be viewed as independent in the occurrence of obesity. Because the gut microbiome is highly dimensional and complex, studies on interactions between gut microbiome and host in obesity are still rare. To explore the relationship of gut microbiome-host interactions with obesity, we performed multi-omics associations of gut metagenome, intestinal transcriptome, and host obesity phenotypes in divergently selected obese-lean broiler lines. Metagenomic shotgun sequencing generated a total of 450 gigabases of clean data from 80 intestinal segment contents of 20 broilers (10 of each line). The microbiome comparison showed that microbial diversity and composition in the duodenum, jejunum, ileum, and ceca were altered variously between the lean- and fat-line broilers. We identified two jejunal microbes (Escherichia coli and Candidatus Acetothermia bacterium) and four cecal microbes (Alistipes sp. CHKCI003, Ruminococcaceae bacterium CPB6, Clostridiales bacterium, and Anaeromassilibacillus sp. An200), which were significantly different between the two lines (FDR < 0.05). When comparing functional metagenome, the fat-line broilers had an intensive microbial metabolism in the duodenum and jejunum but degenerative microbial activities in the ileum and ceca. mRNA-sequencing identified a total of 1,667 differentially expressed genes (DEG) in the four intestinal compartments between the two lines (| log2FC| > 1.5 and FDR < 0.05). Multi-omics associations showed that the 14 microbial species with abundances that were significantly related with abdominal fat relevant traits (AFRT) also have significant correlations with 155 AFRT-correlated DEG (p < 0.05). These DEG were mainly involved in lipid metabolism, immune system, transport and catabolism, and cell growth-related pathways. The present study constructed a gut microbial gene catalog of the obese-lean broiler lines. Intestinal transcriptome and metagenome comparison between the two lines identified candidate DEG and differential microbes for obesity, respectively. Multi-omics associations suggest that abdominal fat deposition may be influenced by the interactions of specific gut microbiota abundance and the expression of host genes in the intestinal compartments in which the microbes reside. Our study explored the interactions between gut microbiome and host intestinal gene expression in lean and obese broilers, which may expand knowledge on the relationships between obesity and gut microbiome.


Prenatal assessment of the antero-posterior jaw relationship in human fetuses: from anatomical to ultrasound cephalometric analysis.
We wished to develop an ultrasound cephalometric analysis, particularly of the antero-posterior jaw relationship, to increase the accuracy of prenatal diagnosis of retrognathism during the routine midterm test. Anatomical cephalometric analysis was performed in 18 formalin-fixed human fetuses (between 16 and 39 gestational weeks), and ultrasound cephalometry was prospectively carried out in 52 pregnant women (21 to 25 gestational weeks). The same landmarks were used in the anatomical and ultrasound median sagittal planes for comparison. Four cephalometric angles were measured relative to the anterior cranial base: alveolar projection of the maxilla and the mandible, chin projection, and facial angle. The antero-posterior jaw discrepancy was calculated. The projection of the maxilla was similar in the two cephalometric analyses (IC [-3.39, 0.23]), whereas the values of the projection of the mandible were lower in the ultrasound sample. The slope of the regression line of the antero-posterior jaw discrepancy on fetuses' age did not show significant differences (IC [-0.05, 1.54]) between anatomical and ultrasound cephalometry, although a difference of 3.23° ± 0.78° (IC [1.69, 4.77]) was observed. Despite this variability, the projections of mandible and chin were well determined by the projection of the maxilla both in the anatomical and ultrasound sample. Cephalometric analysis by prenatal sonography can be performed to study the antero-posterior jaw relationship. We think that this procedure could be useful to improve prenatal diagnosis of retrognathism in high-risk pregnancies. Further studies should address the reproducibility and accuracy of such analysis.


A new application of passive samplers as indicators of in-situ biodegradation processes.
In this paper, a method for evaluating the in-situ degradation of nitro polycyclic aromatic hydrocarbons (nitro-PAH) in sediments is presented. The methodology is adapted from the passive sampler technique, which commonly uses the dissipation rate of labeled compounds loaded in passive sampler devices to sense the environmental conditions of exposure. In the present study, polymeric passive samplers (made of polyethylene strips) loaded with a set of labeled polycyclic aromatic hydrocarbons (PAH) and nitro-PAH were immersed in sediments (in field and laboratory conditions) to track the degradation processes. This approach is theoretically based on the fact that a degradation process induces a steeper concentration gradient of the labeled compounds in the surrounding sediment, thereby increasing their compound dissipation rates compared with their dissipation in abiotic conditions. Postulating that the degradation magnitude is the same for the labeled compounds loaded in polyethylene strips and for their native homologs that are potentially present in the sediment, the field degradation of 3 nitro-PAH (2-nitro-fluorene, 1-nitro-pyrene, 6-nitro-chrysene) was semi-quantitatively analyzed using the developed method.


Immediate and late results of the combined gastrectomy (CG) performance in 719 patients, suffering locally—spread gastric cancer (LSGC), were analyzed. Additional resection of adjacent оrgans was performed in 165 observations. In early postoperative period complications in 116 (16.1%) patients have had occurred, including surgical complications — in 77.7%, and nonsurgical — in 22.3%. Lethality in 30 postoperative days have constituted 11.1%. Тhe patients' postoperative life time was at average (22.9 ± 1.67) mo, mediana— 9.3 mo; indices of 3—year and 5—year survival — (18.9 ± 1.72) and (12.9 ± 1.51)%,accordingly. Essential difference in favor of subtotal distal gastric resection was established, basing on comparison data between this procedure and CG. The data obtained witnessed the expediency of combined operative interventions, what have had widened possibilities of the patients' radical treatment for LSGC.


Effects of a cognition-oriented breast self-examination intervention for Korean women and their spouses.
This study evaluated the effectiveness of a cognition-oriented breast self-examination (BSE) intervention program that is based on the Transtheoretical Model and reflects individual characteristics according to BSE stage among Korean women and their spouses. A time-series nonequivalent control group design was used. SAMPLE AND MEASUREMENT: Twenty-four couples in each of 2 groups completed a preintervention test and were evaluated 1, 3, and 6 months later for their knowledge of breast cancer and BSE, spousal encouragement for BSE, perceived confidence in BSE methods, change in BSE stage, and perceived benefits and barriers to BSE. The intervention involved husbands as well as women, and consisted of lectures on breast cancer and BSE, demonstrations and practice with models while being videotaped, and feedback. There were significant differences between the control and experimental groups for all variables. Change of BSE stage in experimental group showed significantly advancement over time. This intervention program was effective in promoting regular BSE practice and in enhancing confidence in BSE. The intervention also raised awareness among husbands of the importance of breast health for their wives. Educational interventions for breast cancer prevention should be specified to an individual's stage of BSE.


Postactivation Potentiation of Bench Press Throw Performance Using Velocity-Based Conditioning Protocols with Low and Moderate Loads.
This study examined the acute effects of the bench press exercise with low and moderate loads as well as with two predetermined movement velocity loss percentages on bench press throw performance and surface electromyographic (sEMG) activity. Ten trained men completed 5 main trials in randomized and counterbalanced order one week apart. Mean propulsive velocity (MPV), peak velocity (PV) and sEMG activity of prime movers were evaluated before and periodically for 12 minutes of recovery under five conditions: using loads of 40 or 60% of 1 RM, until mean velocity dropped to 90 or 70%, as well as a control condition (CTRL). MPV and PV were increased 4-12 min into recovery by 4.5-6.8% only after the 60%1RM condition during which velocity dropped to 90% and total exercise volume was the lowest of all conditions (p < 0.01, Hedges' g = 0.8-1.7). When peak individual responses were calculated irrespective of time, MPV was increased by 9.2 ± 4.4 (p < 0.001, Hedges' g = 1.0) and 6.1 ± 3.6% (p < 0.001, Hedges' g = 0.7) under the two conditions with the lowest total exercise volume irrespective of the load, i.e. under the conditions of 40 and 60% 1RM where velocity was allowed to drop to 90%. sEMG activity of the triceps was significantly greater when peak individual responses were taken into account only under the 60%1RM condition when velocity dropped to 90% (p < 0.05, Hedges' g = 0.4). This study showed that potentiation may be maximized by taking into account individual fatigue profiles using velocity-based training.


Fixation cells in monkey superior colliculus. II. Reversible activation and deactivation.
1. We tested the hypothesis that a subset of neurons, which we have referred to as fixation cells, located within the rostral pole of the monkey superior colliculus (SC) controls the generation of saccadic eye movements. We altered the activity of these neurons with either electrical stimulation or GABAergic drugs. 2. An increase in the activity of fixation cells in the rostral SC, induced by a train of low-frequency electrical stimulation, delayed the initiation of saccades. With bilateral stimulation the monkey was able to make saccades only after stimulation ceased. 3. Pulses of stimulation delivered during the saccade produced an interruption of the saccade in midflight. The latency to the onset of this perturbation was as short as 12 ms. 4. Injection of the gamma-aminobutyric acid (GABA) antagonist bicuculline into the rostral pole of the SC, which decreases normal GABA inhibition and increases cell activity, increased the latency of saccades to both visual and remembered targets. 5. Injection of the GABA agonist muscimol into the rostral SC, which increases normal GABA inhibition and decreases activity, reduced the latency for saccades to visual targets. The monkey also had difficulty maintaining visual fixation and suppressing unwanted saccades. 6. After muscimol injections, monkeys frequently made very short-latency saccades forming a peak in the saccade latency histogram at < 100 ms. These saccades are similar to express saccades made by normal monkeys. This finding suggests that the fixation cells in the rostral SC are critical for controlling the frequency of express saccades. 7. These results support the hypothesis that fixation cells in the rostral SC inhibit the generation of saccadic eye movements and that they form part of a system of oculomotor control, that of visual fixation.


Gating of afferent input by a central pattern generator.
Intracellular recordings from the sole proprioceptor (the oval organ) in the crab ventilatory system show that the nonspiking afferent fibers from this organ receive a cyclic hyperpolarizing inhibition in phase with the ventilatory motor pattern. Although depolarizing and hyperpolarizing current pulses injected into a single afferent will reset the ventilatory motor pattern, the inhibitory input is of sufficient magnitude to block afferent input to the ventilatory central pattern generator (CPG) for approximately 50% of the cycle period. It is proposed that this inhibitory input serves to gate sensory input to the ventilatory CPG to provide an unambiguous input to the ventilatory CPG.


IgA from HIV+ haemophilic patients triggers intracellular signals coupled to the cholinergic system of the intestine.
IgA was obtained from HIV-infected haemophilic patients and the intracellular signals triggered by its reaction with isolated rat intestinal strips were studied. HIV+ IgA stained intestinal microvilli with a granular immunofluorescence pattern and bound to the muscarinic acetylcholine receptor (mAChR), displacing the specific muscarinic cholinergic antagonist QNB in a non-competitive manner. It triggered the signals that are the consequence of mAChR stimulation in the intestine. Thus, it decreased cAMP synthesis and increased guanosine 3':5'-cyclic monophosphate (cGMP) formation and phosphoinositide (PI) turnover of the intestine. In addition, it stimulated prostaglandin E2(PGE2) synthesis by intestinal strips. Through its effect on PGE2 synthesis, HIV+ IgA could have a dual action. On the one hand, it could enhance immunosuppression at a local level, favouring pathogen growth and subsequent intestinal dysfunction. On the other hand, PGE2 could directly increase intestinal motility and electrolyte/fluid loss. Both effects could be involved in intestinal damage in AIDS.


Enhancement of disaturated phosphatidylcholine synthesis by epidermal growth factor in cultured fetal lung cells involves a fibroblast-epithelial cell interaction.
Epidermal growth factor (EGF) increases the rate of choline incorporation into disaturated phosphatidylcholine in cultured fetal rat type II cells via an indirect mechanism. Whereas-EGF has no effect on the rate of disaturated phosphatidylcholine synthesis when added directly to type II pneumocytes, the growth factor is effective if it is present during preliminary conditioning of the media by lung fibroblasts. This effect is concentration dependent with a maximal effect at 20 ng/ml. When lung fibroblasts are incubated with both glucocorticoids and EGF, there is no significant effect of the growth factor over and above that seen with the steroid alone. This suggests that the two agents might act via a similar mechanism. This is supported by the observation that each inducer leads to the production by lung fibroblasts of a stimulatory factor that has a similar, if not identical, chromatographic elution profile. We conclude that EGF may contribute significantly to the normal onset of lung maturation by elaborating a fibroblast-derived factor that stimulates phosphatidylcholine synthesis in type II pneumocytes.


Purification and properties of mitochondrial malate dehydrogenase from unfertilized eggs of the sea urchin, Anthocidaris crassispina.
Purification and characterization of mitochondrial malate dehydrogenase [EC 188.8.131.52] from unfertilized eggs of the sea urchin, Anthocidaris crassispina, are described. The purification method consisted of dextran sulfate fractionation, Blue Dextran Sepharose chromatography, Phenyl-Sepharose hydrophobic chromatography and DEAE-cellulose chromatography. The enzyme was purified 771-fold with a 7% yield from the crude extract. The purified enzyme appeared homogeneous on polyacrylamide gel electrophoresis under both native and denatured conditions. After incubation at 45 degrees C for 50 min, the enzyme lost about 90% of its activity. In the presence of NADH, however, the enzyme was protected against the heat denaturation. The native enzyme had a molecular weight of about 65,000 and probably consisted of two identical subunits. In the reduction of oxaloacetate with NADH, a broad optimum pH ranging from 8.2 to 9.4 was found with 50 mM Tris-HCl and glycine-NaOH buffers. Sodium phosphate buffer apparently activated the enzyme. The apparent Km values for oxaloacetate and NADH were 19 microM and 30 microM, respectively. The optimum pH for malate oxidation with NAD+ was 10.2 in 50 mM NaHCO3-Na2CO3 buffer. The apparent Km values for malate and NAD+ were 7.0 mM and 0.6 mM, respectively. Zinc ion, sulfite ion, p-chloromercuriphenylsulfonate and adenine nucleotides strongly inhibited the enzyme.


Prevalence of sagittal molar and canine relationships, asymmetries and midline shift in relation to temporomandibular disorders (TMD) in a Finnish adult population.
To examine the prevalence of sagittal relationships, asymmetries and midline shift, and their associations with temporomandibular disorders (TMD) in the Northern Finland Birth Cohort 1966 (NFBC1966). 1845 subjects participated in a clinical examination at the age of 46. Occlusal measurements were performed using 3D models. Symptoms of TMD were screened using validated questions, and signs and diagnoses of TMD were assessed using a modified protocol of the Diagnostic Criteria for TMD (DC/TMD) and questionnaires. Associations between variables of occlusion and TMD were evaluated with χ2-test and Fisher's exact test and using logistic regression analyses, adjusted for self-reported general health, mental health, bruxism, and rheumatoid arthritis. The most common sagittal relationships were Class I and normal canine relationship. Half-cusp Class II and post-normal canine relationship were more frequent in females, and Class III and pre-normal canine relationship in males. Deviations from normal cuspid or molar relationships showed a weak but statistically significant association with TMD, especially in females. Half-cusp Class II and Class II relationships were more frequent in relation to joint-related TMD signs and diagnoses while missing canines were associated with pain-related TMD diagnoses. The present study findings gave some indications that canine relationships are associated with pain-related TMD, whereas Angle II sagittal occlusal relations may associate with joint-related TMD. Occlusal characteristics should therefore be taken into account as one possible associating factor in subjects with TMD.


Reflex stimulation of aortic chemoreceptors through the stellate ganglion during hypoxia and hypotension in cats.
1. In cats anaesthetized with sodium pentobarbitone (35 mg kg-1), an investigation was made of the mechanisms underlying the enhancement of aortic chemoreceptor activity through the excitatory effect mediated by the sympathetic outflow to them during hypoxia and hypotension. 2. Removal of the right stellate ganglion significantly (P < 0.01) reduced the responses of the chemoreceptors to hypoxia and hypotension. Injection of a bolus of sodium pentobarbitone reduced the responses before, but not after, stellectomy. This indicated that the excitatory sympathetic influence on the chemoreceptors (attributed to glomeral vasoconstriction leading to reduction in blood flow) is exerted entirely through the right stellate ganglion. This excitatory effect was abolished after cutting the vagi and both carotid sinus nerves. 3. It is concluded that, in addition to the direct excitatory effect of hypoxia on aortic chemoreceptors, a reflex chemoreceptor excitatory component is mediated through the vagi, carotid sinus nerves and right stellate ganglion.


Echocardiographic examination of women previously treated with fenfluramine: long-term follow-up of a randomized, double-blind, placebo-controlled trial.
Fenfluramine hydrochloride was withdrawn from the market in September 1997 after reports of heart valve abnormalities in patients who used it. The prevalence of echocardiographic abnormalities and the clinical cardiovascular status of patients who received fenfluramine monotherapy remains uncertain. A long-term, follow-up evaluation was undertaken in subjects who were randomly assigned to receive either fenfluramine hydrochloride (60 mg daily) or placebo as part of a double-blind smoking cessation therapy study. Cardiovascular status was evaluated by echocardiography, medical history, and physical examination. From the group of 720 smokers who had originally participated in the smoking cessation therapy trial, 619 women were enrolled; data from 530 (276 in the fenfluramine group and 254 in the placebo group) were evaluable. No statistically significant differences were identified in the prevalence of aortic or mitral regurgitation by Food and Drug Administration criteria or by grade, aortic or mitral valve leaflet mobility restriction or thickening, elevated pulmonary artery systolic pressure, or abnormal left ventricular ejection fraction. No significant differences were demonstrated in cardiovascular status by physical examination, and no serious cardiac events were noted among fenfluramine-treated subjects. There was no evidence of drug-related heart disease up to 4.9 years after anorexigen therapy in subjects who were randomly assigned to receive fenfluramine at the recommended dose for up to 3 months.


Gall bladder cancer, extrahepatic bile duct cancer and ampullary carcinoma in New Zealand: Demographics, pathology and survival.
The aim of present paper was to document the incidence of gall bladder cancer, cancer of the extrahepatic bile ducts and ampullary carcinoma in New Zealand. Data were collected from the New Zealand Cancer Registry from 1980 to 1997 and combined with national census statistics to give crude and age standardized incidence rates. Over the 18-year study period, 226 carcinomas of the ampulla of Vater, 608 gall bladder cancers, and 486 extrahepatic cholangiocarcinomas were registered. The age standardized incidence rates for gall bladder carcinoma in all New Zealanders were 0.41/100 000 in men and 0.74/100 000 in women. The age standardized incidence rates for gall bladder cancer in Maori were 1.49/100 000 in Maori men and 1.59/100 000 in Maori women. The corresponding age standardized incidence rates for extrahepatic bile duct cancers were 0.67/100 000 in men and 0.45/100 000 in women. There were insufficient cases to calculate an age standardized incidence in Maori or Pacific Islanders. For carcinoma of the ampulla, the age standardized rates were 0.34/100 000 in men and 0.25/100 000 in women. There were insufficient cases to calculate an age standardized incidence rate for Maori or Pacific Islanders. When histology was defined adenocarcinoma was the most common form of cancer occurring in 66% of gall bladder cancers, 91% of extrahepatic bile duct cancers and 70% of ampullary cancers. Most tumours were advanced at presentation with regional or distant metastases present in 72% of gall bladder cancers, 63% of extrahepatic bile duct cancers and 69% of ampullary tumours at diagnosis. Survival was poor with median survivals of 86 days, 151 days and 440 days recorded for gall bladder cancer, extrahepatic bile duct cancer and ampullary cancer, respectively. The demographic profile, pathology and survival of patients with gall bladder cancer, extrahepatic bile duct cancer and ampullary carcinoma are similar in New Zealand to that of other Western countries. However New Zealand Maori have a relatively high incidence of gall bladder cancer, and the incidence is equal in both Maori men and women, while cancers of the extra-hepatic bile duct and ampulla of Vater are rare in Maori. In comparison, cancers of the gall bladder, extrahepatic bile ducts and ampulla are rare in Pacific Islanders.


Influence of Religiosity on Youths' Attitudes Towards People with Disabilities in the United Arab Emirates.
This cross-sectional survey investigates the influence of youths' religiosity on their attitude towards people with disabilities. The Muslim religiosity questionnaire and multidimensional attitudes scale towards persons with disabilities were used to survey 733 youths from the federal university in the United Arab Emirates. The results indicated that the youths were religious and had positive attitudes towards people with disabilities. An increase in religiosity is associated with a positive attitude towards disability, and both religiosity and total family income positively impacted the attitude towards people with disabilities. Reducing inequalities by including persons with disabilities is one of the UN 2030 Agenda for Sustainable Development objectives. Policies should aim to enhance curriculum, improvise public guidelines and partner with associated faith-based leaders to build an inclusive society for people with disabilities, thus helping to achieve sustainable development goals.


Witchcraft beliefs and witch hunts: an interdisciplinary explanation.
This paper proposes an interdisciplinary explanation of the cross-cultural similarities and evolutionary patterns of witchcraft beliefs. It argues that human social dilemmas have led to the evolution of a fear system that is sensitive to signs of deceit and envy. This was adapted in the evolutionary environment of small foraging bands but became overstimulated by the consequences of the Agricultural Revolution, leading to witch paranoia. State formation, civilization, and economic development abated the fear of witches and replaced it in part with more collectivist forms of social paranoia. However, demographic-economic crises could rekindle fear of witches-resulting, for example, in the witch craze of early modern Europe. The Industrial Revolution broke the Malthusian shackles, but modern economic growth requires agricultural development as a starting point. In sub-Saharan Africa, witch paranoia has resurged because the conditions for agricultural development are lacking, leading to fighting for opportunities and an erosion of intergenerational reciprocity.


Influence of smoking heating up tobacco products and e-cigarettes on the microbiota of dental plaque.
Electronic nicotine delivery devices (ENDDs) are getting more and more popular among adolescents and young people under 25, signifying the beginning of tobacco product use for many of them. The state of the local microbiota can be affected by a large number of factors, namely the inhaled aerosol temperature, the oral cavity ph, the diet nature, genetics, etc. The aim of the study was to identify the changes of dental microbiocenosis among adolescents who use devices for heating tobacco products and vape. The study was perfomed in 65 adolescents, aged 14 to 18, who were divided into three groups: the first (control) group consisted of 20 non-smokers, the second group comprised 25 patients who used a tobacco heating system, and the third group - 20 subjects who used electronic vape cigarettes. For microbiological examination, the swabs from the teeth cervical region plaque were taken. The control group was dominated by S. mitis (10 strains - 35.7%), followed by E. faecium (5 strains - 17.9%) and E. coli (4 strains - 14.3%). For heating tobacco, the most common were S. mitis (11 strains - 23.9%), S. aureus (6 strains - 13.0%) and E. faecium and C. xerosis (5 strains - 10.9%). Among the vape systems users, the most common species was S. pneumoniae (17.9%), followed by S. mitis, E. faecium and C. xerosis (12.8% each). The use of electronic smoking systems reduces the number of resident plaque microflora by increasing the excretion frequency and the emergence of opportunistic transient streptococci, namely S. pneumoniae and S. pyogenes with an epidemiologically significant level of colonization.


[Antiproliferative effects on Ph+ leukemic cells transfected with antisense bcr/abl fusion gene].
To investigate the possible roles that bcr/abl fusion gene plays in Ph-chromosome positive leukemia cells, in this study the recombinant plasmids expressing antisense transcripts to bcr/abl fusion gene were transfected into K562 and BV173 cell lines by lipofectin reagent. Southern and Northern bilot hybridizations proved the integration and expression of exogenous DNA in target cells. Antisense transcripts to bcr/abl inhibited proliferation and colony-forming ability of target cells. Through flow cytometric cell cycle analysis it was found that during the early period of transfection decrease of cells in G0/G1 and S phases and increase in G2 phase were observed, suggesting block of G2 progression. Later, cells in G0/G1 phase decreased further and retardation of S and G2 progressions was obvious. The results also indicated that proliferative inhibition of target cells was accompanied by genomic DNA degradation.


Advanced diffuse malignant peritoneal mesothelioma responding to palliative chemotherapy.
A 64-year-old man diagnosed with advanced malignant peritoneal mesothelioma by laparoscopic biopsy was treated with systemic chemotherapy. The patient underwent first-line chemotherapy with pemetrexed plus cisplatin for 11 months, then second-line chemotherapy with gemcitabine plus vinorelbine for 6 months, and third-line chemotherapy with CPT-11 for 4 months. After third-line chemotherapy failed, he received palliative treatment. Although the tumor continued to grow, and he died 24 months after initiation of treatment, chemotherapy prolonged the survival time and improved his quality of life.


Nicotine binding to brain tissue from drug-naive and nicotine-treated rats.
Two nicotine binding sites with dissociation constants for nicotine of approximately 3 nM and 12 microM respectively have been found in homogenates of rat hippocampus, hypothalamus, parietal cortex and mesencephalon, the greatest density of high affinity binding sites being in parietal cortex (30.0 +/- 3.0 fmol (mg protein)-1), the lowest in hypothalamus (16.1 +/- 1.0 fmol (mg protein)-1). The density of the low affinity sites (approx. 20 pmol (mg protein)-1) did not show any regional variation. Neither site was present in homogenates of medulla oblongata. The accumulation of radioactivity following the subcutaneous administration of [3H]nicotine (0.4 mg kg-1) was rapid, the highest concentrations being found in the brain regions with the highest density of high affinity binding sites. Medulla oblongata did not accumulate radioactivity above the concentration found in plasma. The chronic administration of nicotine (0.4 mg kg-1 s.c. daily for 39 days) had no significant effects on [3H]nicotine binding to brain tissue or its accumulation into brain following subcutaneous administration. It is concluded that nicotine readily passes from plasma into brain tissue and is accumulated in the areas containing high affinity binding sites for the compound. It is also concluded that the biochemical and behavioural effects reported previously in response to the chronic daily administration of nicotine do not depend upon changes in its uptake or binding by brain tissue.


[Trend in the study of cocaine addiction].
Psychostimulant drugs including cocaine increase extracellular levels of monoamines by blocking the neuronal plasma membrane transporters. Increased extracellular dopamine levels in mesocorticolimbic dopamine systems have been postulated to mediate the rewarding effects of cocaine. Studies in genetically modified mice models, particularly knockout mice have contributed a great deal to our understanding of the mechanisms underlying psychostimulant actions. Phenotypic analysis of genetically modified mice models has been instrumental in identifying the role of specific molecular targets of cocaine. In this article, we summarize studies that have reported the effects of cocaine using genetically modified mice especially gene knockouts of the monoamine transporters and receptors.


Evidence for Acute Myocardial and Skeletal Muscle Injury after Serial Transthoracic Shocks in Healthy Swine.
Previous serological studies have shown controversial results whether defibrillation or cardioversion can cause myocardial injury. Cardiovascular Magnetic Resonance (CMR) can be used to detect myocardial edema, hyperemia and capillary leak as features of acute myocardial injury. The aim of this study was to assess for myocardial and skeletal muscle injury in swine following transthoracic shocks. Seventeen anaesthetized swine were examined, with 11 undergoing five synchronized transthoracic shocks (200J). Myocardial and skeletal muscle injury were assessed at baseline and up to 5h post-shock employing T1 mapping, T2 mapping, early and late gadolinium enhancement. Serologic markers (cFABP, TnI, CK, and CK-MB) and myocardial tissue were assessed by standard histology methods. In myocardial regions within the shock path, T1 and T2 were significantly increased compared to remote myocardium in the same animals. The early gadolinium enhancement ratio between the left-ventricular myocardium and the right pectoral muscle was also increased compared to control animals. After the shocks cFABP and CK were significantly elevated. After shock application, the regions identified as abnormal by CMR showed significantly increased interstitial and myocardial cell areas in histological analysis. This increased cell area suggests significant cellular and interstitial edema. Our pilot study data indicate that serial defibrillator shocks lead to acute skeletal muscle and myocardial injury. CMR is a useful tool to detect and localize myocardial and skeletal muscle injury early after transthoracic shocks in vivo. In the future the technique could potentially be used as an additional tool for quality control such as verifying insufficient local shock application in non-responders after cardioversion or to develop safer shock forms.


Smallholder responses to climate anomalies in rural Uganda.
Recent research suggests that sub-Saharan Africa will be among the regions most affected by the negative social and biophysical ramifications of climate change. Smallholders are anticipated to respond to rising temperatures and precipitation anomalies through on-farm management strategies and diversification into off-farm activities. Few studies have empirically examined the relationship between climate anomalies and rural livelihoods. Our research explores the impact of climate anomalies on farmers' on and off-farm livelihood strategies, considering both annual and decadal climate exposures, the relationship between on and off-farm livelihoods, and the implications of these livelihood strategies for agricultural productivity. To examine these issues, we link gridded climate data to survey data collected in 120 communities from 850 Ugandan households and 2,000 agricultural plots in 2003 and 2013. We find that smallholder livelihoods are responsive to climate exposure over both short and long time scales. Droughts decrease agricultural productivity in the short term and reduce individual livelihood diversification in the long term. Smallholders cope with higher temperatures in the short term, but in the long run, farmers struggle to adapt to above-average temperatures, which lower agricultural productivity and reduce opportunities for diversification. On and off-farm livelihood strategies also appear to operate in parallel, rather than by substituting for one another. These observations suggest that in order to sustain rural livelihoods, new strategies will be necessary if smallholders are to successfully adapt to climate change.


Intermittent fasting contributes to aligned circadian rhythms through interactions with the gut microbiome.
The timing of food consumption is considered to be an important modulator of circadian rhythms, regulating a wide range of physiological processes which are vital to human health. The exact mechanisms underlying this relationship are not fully understood, but likely involve alterations in the structure and functioning of the gut microbiome. Therefore, this narrative review aims to clarify these mechanisms by focusing on intermittent fasting as a dietary strategy of food timing. A literature search identified 4 clinical and 18 preclinical studies that examined either (1) the impact of intermittent fasting on the gut microbiome, or (2) whether circadian rhythms of the host are subject to changes in the bacterial populations in the gut. Results reveal that intermittent fasting directly influences the gut microbiome by amplifying diurnal fluctuations in bacterial abundance and metabolic activity. This in turn leads to fluctuations in the levels of microbial components (lipopolysaccharide) and metabolites (short-chain fatty acids, bile acids, and tryptophan derivates) that act as signalling molecules to the peripheral and central clocks of the host. Binding of these substrates to pattern-recognition receptors on the surface of intestinal epithelial cells in an oscillating manner leads to fluctuations in the expression of circadian genes and their transcription factors involved in various metabolic processes. Intermittent fasting thus contributes to circadian rhythmicity in the host and could hold promising implications for the treatment and prevention of diseases associated with disordered circadian rhythms, such as obesity and metabolic syndrome. Future intervention studies are needed to find more evidence on this relationship in humans, as well as to clarify the optimal fasting regimen for balanced circadian rhythms.


Song as an indicator of parasitism in the sedge warbler.
We studied female choice and reproductive success in a marked population of sedge warblers Acrocephalus schoenobaenus, from 1995 to 1996. Three genera of parasitic blood protozoans, namely Haemoproteus sp. Trypanosoma sp. Plasmodium sp., were identified from blood samples taken from all breeding adults. Relatively high prevalence values of 19.5% in 1995 and 37.5% in 1996 were associated with increased levels of white blood cells relative to the number of red blood cells. Compared with nonparasitized males, parasitized males had significantly lower repertoire sizes in both years of the study; in one year, they also spent less time in song flights and weighed less. They also provisioned their broods at a lower rate. Parasitized females produced the same clutch size as nonparasitized females, although their broods were smaller at 7 days old. We suggest that haematozoan infections may reduce the expression of sexually selected song traits. Furthermore, such infections may influence the standard of parental care provided by males, although further research is needed to determine whether this is mediated through genetic resistance to parasitism or the effects of parasitism upon immediate body condition. Copyright 1999 The Association for the Study of Animal Behaviour.


Current Challenges in the Peripartum Management of Women with von Willebrand Disease.
For many women, pregnancy and childbirth represent their first major hemostatic challenges. Despite advancements in obstetric care, up to 2 to 5% of all deliveries are complicated by postpartum hemorrhage (PPH). To mitigate bleeding risk, physiological changes occur in pregnancy, including increases in plasma von Willebrand factor (VWF) and factor VIII levels. For women with von Willebrand disease (VWD), these physiological alterations are blunted or absent. As a result, women with VWD have a heightened risk of PPH, both primary (in the first 24 hours) and secondary (>24 hours to 6 to 12 weeks postpartum). Pregnancy and delivery management for women with VWD should therefore be carefully coordinated as part of a multidisciplinary team approach. In the absence of large-scale clinical trials, the management of women with VWD during pregnancy is guided by expert consensus guidelines. Clinical practices internationally are not uniform, and areas of considerable clinical uncertainty exist. Traditional peripartum plasma VWF thresholds for hemostatic cover and therapeutic targets are currently under scrutiny, as PPH is not eliminated in women with VWD who receive replacement therapy. The benefit and optimal duration of postpartum tranexamic acid have yet to be defined, and standardized methods of quantification of blood loss at the time of delivery are currently lacking. In this article, we review the evidence base to date and explore the current clinical challenges in the management of pregnant women with VWD.


A dehydratase domain in ambruticin biosynthesis displays additional activity as a pyran-forming cyclase.
Hydropyran rings are a common structural motif in reduced polyketides. Information on their biosynthetic formation and particularly the biochemical characterization of the responsible enzymes has only been reported in few cases. The dehydratase domain AmbDH3 from the ambruticin polyketide synthase was investigated. Through in vitro assay of the recombinant domain with synthetically-derived substrate surrogates, it was shown that it has a second catalytic activity as a cyclase that performs oxa-conjugate addition. Probing AmbDH3 with synthetic substrate analogues revealed stereoselectivity and substrate tolerance in both substeps. This is the first characterization of a pyran-forming cyclase from a cis-AT PKS system and the first report of a polyketide synthase domain with this kind of dual activity. Finally, it was revealed that this domain shows potential for application in chemoenzymatic synthesis.


Performance Comparison of Different Analytic Methods in Proficiency Testing for Mutations in the BRAF, EGFR, and KRAS Genes: A Study of the College of American Pathologists Molecular Oncology Committee.
The performance of laboratory testing has recently come under increased scrutiny as part of important and ongoing debates on regulation and reimbursement. To address this critical issue, this study compares the performance of assay methods, using either commercial kits or assays designed and implemented by single laboratories ("home brews"), including next-generation sequencing methods, on proficiency testing provided by the College of American Pathologists Molecular Oncology Committee. To compare the performance of different assay methods on College of American Pathologists proficiency testing for variant analysis of 3 common oncology analytes: BRAF, EGFR, and KRAS. There were 6897 total responses across 35 different proficiency testing samples interrogating 13 different variants as well as wild-type sequences for BRAF, EGFR, and KRAS. Performance was analyzed by test method, kit manufacturer, variants tested, and preanalytic and postanalytic practices. Of 26 reported commercial kits, 23 achieved greater than 95% accuracy. Laboratory-developed tests with no kit specified demonstrated 96.8% or greater accuracy across all 3 analytes (1123 [96.8%] acceptable of 1160 total responses for BRAF; 848 [97.5%] acceptable of 870 total responses for EGFR; 942 [97.0%] acceptable of 971 total responses for KRAS). Next-generation sequencing platforms (summed across all analytes and 2 platforms) demonstrated 99.4% accuracy for these analytes (165 [99.4%] acceptable of 166 total next-generation sequencing responses). Slight differences in performance were noted among select commercial assays, dependent upon the particular design and specificity of the assay. Wide differences were noted in the lower limits of neoplastic cellularity laboratories accepted for testing. These data demonstrate the high degree of accuracy and comparable performance across all laboratories, regardless of methodology. However, care must be taken in understanding the diagnostic specificity and reported analytic sensitivity of individual methods.


Figure of merit for environmental SEM and its implications.
A recently introduced figure of merit for environmental and low vacuum scanning electron microscopes has now been computed in the full operational pressure range for one commercial instrument. The direct simulation Monte Carlo method has been used in lieu of experimental measurements. The theory of this figure of merit is further consolidated. It is shown that a thin pressure limiting aperture can indeed be used as an optimum reference system for all instruments employing differential pumping in the transfer of an electron beam from high vacuum to high pressure. The implications of the results obtained are discussed both in relation to existing commercial instruments and associated literature to pave the way for future progress in the field.


Diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP) in children and adolescents: experience in a single institution.
Experience in the use of endoscopic retrograde cholangiopancreatography (ERCP) for the investigation and treatment of pancreaticobiliary disorders is relatively limited in children. This report reviews the experience in a single institution with pediatric ERCPs and documents the indications, success rate, diagnostic and therapeutic yields, complications, and the impact on patient management. The data of all consecutive patients aged < or = 18 years who underwent ERCP procedures between the years 1997 and 2007 were retrospectively identified through a computer database search. The database prospectively recorded the indications, findings, therapies, and complications. During the study period, 32 ERCP procedures were performed in 28 children with a median age of 13 (range 8 - 18) years. ERCPs were performed for biliary pathology in 21 (75 %) and for pancreatic pathology in 7 (25 %) patients. The most common biliary indications were suspected choledocholithiasis and postoperative bile leaks. Hydatid disease was the most common diagnosis that yielded bile leaks. The pancreatic indications were recurrent pancreatitis and traumatic pancreatic duct disruption. Cannulation of the desired duct was successful in all procedures. An endoscopic sphincterotomy, stone/sludge removal or a stent placement was performed in 20 (63 %) procedures. According to the long-term follow-up, avoidance from any further surgical interventions was achieved in 11 (65 %) children, in whom ERCP was undertaken as a therapeutic intervention. The complication rate was 6 % with the development of mild self-resolving pancreatitis in one patient and stent occlusion in another. ERCP in the pediatric population has a high success rate, both as a diagnostic tool and for therapeutic interventions, provided it is performed by experienced endoscopists. The delicate delineation of the anatomy by ERCP and its therapeutic potential make it absolutely superior to other less invasive tools such as magnetic resonance cholangiopancreatography.


The acoustic startle response is normal in patients with multiple system atrophy.
We investigated the acoustic startle response in eight patients with MSA and compared the results with those from a group of age matched healthy subjects. Onset latency and amplitude of the responses obtained in the orbicularis oculi, masseter and sternocleidomastoid muscles were not different in patients and control subjects. We conclude that, in spite of the pathological derangement described in brainstem reticular nuclei in MSA, the neuronal circuits mediating the auditory startle reflex are functionally preserved.


Evidence that thymectomized, bone marrow-reconstituted rats do not reject their allografts.
We have investigated the reasons why thymectomized, bone marrow-reconstituted (B) rats do not reject their allografts, by comparing the structure of inflammation and functions of inflammatory cells in nonrejecting allografts to rejecting allografts in normal control recipients. The results demonstrate that B recipients mount a specific cellular response towards the graft. The response in B recipients differs from that in normal controls by a smaller intensity of inflammation, fewer blast cells, and activated mononuclear phagocytes in the inflammatory infiltrate, as well as a delay in the appearance of specific donor-directed lytic activity in the graft. B rats also have fewer blast cells and an inverted CD4/8 ratio in the spleen. There is no obvious absence of any given cell type or cellular function in the graft inflammatory infiltrate. In light of these results no cell type responsible for allograft nonrejection can be pinpointed.


Condensed Tannins in White Clover (Trifolium repens) Foliar Tissues Expressing the Transcription Factor TaMYB14-1 Bind to Forage Protein and Reduce Ammonia and Methane Emissions in vitro.
Grazing ruminants contribute to global climate change through enteric methane and nitrous oxide emissions. However, animal consumption of the plant polyphenolics, proanthocyanidins, or condensed tannins (CTs) can decrease both methane emissions and urine nitrogen levels, leading to reduced nitrous oxide emissions, and concomitantly increase animal health and production. CTs are largely absent in the foliage of important temperate pasture legumes, such as white clover (Trifolium repens), but found in flowers and seed coats. Attempts at enhancing levels of CT expression in white clover leaves by mutagenesis and breeding have not been successful. However, the transformation of white clover with the TaMYB14-1 transcription factor from Trifolium arvense has resulted in the production of CTs in leaves up to 1.2% of dry matter (DM). In this study, two generations of breeding elevated foliar CTs to >2% of DM. The CTs consisted predominantly of prodelphinidins (PD, 75-93%) and procyanidins (PC, 17-25%) and had a mean degree of polymerization (mDP) of approximately 10 flavan-3-ol subunits. In vitro studies showed that foliar CTs were bound to bovine serum albumin and white clover proteins at pH 6.5 and were released at pH 2.-2.5. Using rumen in vitro assays, white clover leaves containing soluble CTs of 1.6-2.4% of DM significantly reduced methane production by 19% (p ≤0.01) and ammonia production by 60% (p ≤ 0.01) relative to non-transformed wild type (WT) controls after 6 h of incubation. These results provide valuable information for further studies using CT expressing white clover leaves for bloat prevention and reduced greenhouse gas emissions in vivo.


Carbamazepine poisoning: elimination kinetics and quantitative relationship with carbamazepine 10,11-epoxide.
Carbamazepine (amizepine) is a widely used psychotropic agent. A much easier accessibility of this drug, observed during the recent years, may account for an increasing number of acute intoxications with carbamazepine. The aim of this study was to determine the elimination kinetics of carbamazepine and its metabolite carbamazepine 10,11-epoxide, and to identify the quantitative relationship between concentrations of these compounds, in serum. The subjects were 41 patients with acute carbamazepine intoxication. Serum carbamazepine and carbamazepine 10,11-epoxide concentrations were determined every 6 hours during thefirst 24 hours of hospitalization, and then every 12 hours. At the same time, urinalyses were performed for each patient to confirm or exclude homogeneity of poisoning. Depending on the type of intoxication (homogenous or combined), three groups of patients, and on the method of treatment (symptomatic, charcoal administration), two groups of patients were distinguished. The statistical analysis of the results revealed that among the investigated parameters (time-integrated concentrations of carbamazepine and carbamazepine 10,11-epoxide in serum, the presence of drugs, and/or ethanol, charcoal treatment) only carbamazepine concentrations had statistically significant effect on the duration of coma regarded as a critical effect. The kinetics of carbamazepine elimination was determined on the basis of the mean carbamazepine concentrations at the same timing of sampling for each patient in all the three groups; the mean carbamazepine elimination in serum followed zero-order kinetics. In individual groups, the decrease in serum carbamazepine concentrations ranged from 0.5 to 0.8 mg L(-1) hour(-1). Contrary to the suggestions found in the literature, carbamazepine 10,11-epoxide determination does not seem to enhance the possibility of anticipating the course of intoxication or the time of recovery.


Exercise-induced modulation of myokine irisin in bone and cartilage tissue-Positive effects on osteoarthritis: A narrative review.
Osteoarthritis is a chronic degenerative musculoskeletal disease characterized by pathological changes in joint structures along with the incidence of which increases with age. Exercise is recommended for all clinical treatment guidelines of osteoarthritis, but the exact molecular mechanisms are still unknown. Irisin is a newly discovered myokine released mainly by skeletal muscle in recent years-a biologically active protein capable of being released into the bloodstream as an endocrine factor, the synthesis and secretion of which is specifically induced by exercise-induced muscle contraction. Although the discovery of irisin is relatively recent, its role in affecting bone density and cartilage homeostasis has been reported. Here, we review the production and structural characteristics of irisin and discuss the effects of the different types of exercise involved in the current study on irisin and the role of irisin in anti-aging. In addition, the role of irisin in the regulation of bone mineral density, bone metabolism, and its role in chondrocyte homeostasis and metabolism is reviewed. A series of studies on irisin have provided new insights into the mechanisms of exercise training in improving bone density, resisting cartilage degeneration, and maintaining the overall environmental homeostasis of the joint. These studies further contribute to the understanding of the role of exercise in the fight against osteoarthritis and will provide an important reference and aid in the development of the field of osteoarthritis prevention and treatment.


Fully uncomplexed cyclodextrin in mixed systems of vesicle-cyclodextrin: solvolysis of benzoyl chlorides.
In this contribution the influence of beta-cyclodextrin (CD) on the behavior of aqueous systems containing vesicles of dipalmitoyl phosphatidyl choline (DPPC) has been studied by determining the kinetics of the solvolysis reaction of substituted benzoyl chlorides whose solvolysis reactivity entails a high sensitivity on media properties. The application of the pseudophase formalism allowed us to obtain the thermodynamic and kinetic coefficients characteristic of the reaction, which are essentially independent of the concentration of CD. We were able to determine the percentages of uncomplexed cyclodextrin in equilibrium with the vesicular system which were in all cases compatible with 100%. The obtained results led us to conclude that the properties of DPPC vesicles are not affected by the presence of CD in the medium and there is no type of interaction between the CD and the vesicular surfactant monomers and, therefore, all cyclodextrin is present in the mixed system as uncomplexed cyclodextrin.


Extensive study on electrocution at the Bureau of Legal Medicine of Milan (1993-2017): Determination of the current mark with scanning electron microscope/energy-dispersive X-ray analysis on paraffin-embedded samples.
Literature on electrocution in Italy is limited. The authors have focused their attention on the use of scanning electron microscope/energy-dispersive X-ray analysis in order to evaluate the current mark even on paraffin-embedded samples. A total of 24,104 autopsies were performed at the Section of Legal Medicine of Milan (1993-2017); all cases of death caused by electrocution (low and high voltage) were selected. We assessed a regular histological examination, a toxicological examination and detected metallisation with energy-dispersive X-ray spectroscopy analysis on paraffin-embedded tissues of typical current marks. We collected 27 high-voltage fatalities and five cases of low-voltage suicide electrocution; the technique revealed itself as sensitive. In all cases, microscopic examination highlighted the typical signs of electric current and thermal damage but the histochemical specific stainings for copper and iron gave negative results. Scanning electron microscope/energy-dispersive X-ray analysis, assessed on these same samples, even when paraffin-embedded, however, enabled us to detect these elements and differentiate between the various metal residues involved in the electrocution process. Based on their experience, authors advise the use of scanning electron microscope/energy-dispersive X-ray analysis on electrocution deaths to provide information for forensic diagnosis.


Slow local movements of collagen fibers by fibroblasts drive the rapid global self-organization of collagen gels.
Aclassic model for tissue morphogenesis is the formation of ligament-like straps between explants of fibroblasts placed in collagen gels. The patterns arise from mechanical forces exerted by cells on their substrates (Harris et al., 1981). However, where do such straps come from, and how are slow local movements of cells transduced into dramatic long-distance redistributions of collagen? We embedded primary mouse skin and human periodontal ligament fibroblasts in collagen gels and measured the time course of patterning by using a novel computer algorithm to calculate anisotropy, and by tracking glass beads dispersed in the gel. As fibroblasts began to spread into their immediate environments, a coordinated rearrangement of collagen commenced throughout the gel, producing a strap on a time scale of minutes. Killing of cells afterwards resulted in a partial relaxation of the matrix strain. Surprisingly, relatively small movements of collagen molecules on the tensile axis between two pulling explants induced a much larger concomitant compression of the gel perpendicular to the axis, organizing and aligning fibers into a strap. We propose that this amplification is due to the geometry of the collagen matrix, and that analogous amplified movements may drive morphological changes in other biological meshes, both outside and inside the cell.


Anti-Cancer Properties of Coix Seed Oil against HT-29 Colon Cells through Regulation of the PI3K/AKT Signaling Pathway.
This study aims to observe the effects of coix seed oil (CSO) on HT-29 cells and investigate its possible regulation mechanism of the PI3K/Akt signaling pathway. Fatty acid analysis showed that coix seed oil mainly contains oleic acid (50.54%), linoleic acid (33.76%), palmitic acid (11.74%), and stearic acid (2.45%). Fourier transform infrared results found that the fatty acid functional groups present in the oil matched well with the vegetable oil band. The results from CCK-8 assays showed that CSO dose-dependently and time-dependently inhibited the viability of HT-29 cells in vitro. CSO inhibited cell viability, with IC50 values of 5.30 mg/mL for HT-29 obtained after 24 h treatment. Morphological changes were observed by apoptotic body/cell nucleus DNA (Hoechst 33258) staining using inverted and fluorescence microscopy. Moreover, flow cytometry analysis was used to evaluate the cell cycle and cell apoptosis. It showed that CSO induced cell apoptosis and cycle arrest in the G2 phase. Quantitative real-time PCR and Western blotting revealed that CSO induced cell apoptosis by downregulating the PI3K/AKT signaling pathway. Additionally, CSO can cause apoptosis in cancer cells by activating caspase-3, up-regulating Bax, and down-regulating Bcl-2. In conclusion, the results revealed that CSO induced G2 arrest and apoptosis of HT-29 cells by regulating the PI3K/AKT signaling pathway.


Home-based neonatal care by community health workers for preventing mortality in neonates in low- and middle-income countries: a systematic review.
The objective of this review is to assess the effect of home-based neonatal care provided by community health workers (CHWs) for preventing neonatal, infant and perinatal mortality in resource-limited settings with poor access to health facility-based care. The authors conducted a systematic review, including meta-analysis and meta-regression of controlled trials. The data sources included electronic databases, with a hand search of reviews, abstracts and proceedings of conferences to search for randomized, or cluster randomized, controlled trials evaluating the effect of home-based neonatal care provided by CHWs for preventing neonatal, infant and perinatal mortality. Among the included trials, all from South Asian countries, information on neonatal, infant and perinatal mortality was available in five, one and three trials, respectively. The intervention package comprised three components, namely, home visits during pregnancy (four trials), home-based preventive and/or curative neonatal care (all trials) and community mobilization efforts (four trials). Intervention was associated with a reduced risk of mortality during the neonatal (random effects model relative risk (RR) 0.75; 95% confidence intervals (CIs) 0.61 to 0.92, P=0.005; I(2)=82.2%, P<0.001 for heterogeneity; high-quality evidence) and perinatal periods (random effects model RR 0.78; 95% CI 0.64 to 0.94, P=0.009; I(2)=79.6%, P=0.007 for heterogeneity; high-quality evidence). In one trial, a significant decline in infant mortality (RR 0.85; 95% CI 0.77 to 0.94) was documented. Subgroup and meta-regression analyses suggested a greater effect with a higher baseline neonatal mortality rate. The authors concluded that home-based neonatal care is associated with a reduction in neonatal and perinatal mortality in South Asian settings with high neonatal-mortality rates and poor access to health facility-based care. Adoption of a policy of home-based neonatal care provided by CHWs is justified in such settings.


Patterns of improvement in depressive symptoms with fluoxetine treatment.
By definition, patients who respond to antidepressant treatment show significant improvements in most, if not all, of their depressive symptoms. We assessed the patterns of change in depressed outpatients treated openly with fluoxetine 20 mg/day for 8 weeks. We studied 62 depressed outpatients with major depressive disorder who showed full response following fluoxetine treatment. Analysis of the data revealed that the symptoms that tended to improve relatively early during treatment were suicidal ideation, excessive guilt, and lack of appetite. Our tentative conclusion from this pilot study was that symptom improvement tends to occur in both cognitive and neurovegetative areas early in treatment as well as later.


Evaluation of Nutritional Status of Colorectal Cancer Patients from Algerian East Using Anthropometric Measurements and Laboratory Assessment.
Chemotherapy may lead to cancer patient malnutrition, associated with reduced response, and increased complications to anticancer therapy. This study aimed to evaluate the nutritional status of Algerian colorectal cancer patients. This cross-sectional study was conducted during 2016-2017 at the Oncology departments from the Algerian East included 90 patients with colorectal cancer. For each patient, a questionnaire, anthropometric measurements and biochemical tests have been done. The 50-59 yr and 60-69 age groups represented more than half of the population. Obesity and underweight were significantly higher in female patients according to their actual Body mass index (BMI). Prevalence of underweight increased after cancer diagnosis, while obesity prevalence has decreased significantly. The malnutrition classification based on Mid-upper-arm muscle circumference (MUAMC) and the triceps skinfold thickness (TST) has shown a significant higher prevalence of malnutrition among male patients than females. The classification of Nutrition risk index (NRI) has shown a significant high percentage of male patients having malnutrition. In our study, no significant differences were recorded for biochemical tests. Anemia recorded the higher prevalences for both sex compared to other deficiency. Hypoironemia prevalence's was higher among male patients than females while hypokalemia and hypoproteinemia prevalence's were higher in female patients. Malnutrition in CRC patients must be combated by early detection to decrease complications associated to cancer and chemotherapy.


Stimulation of Let-7 Maturation by Metformin Improved the Response to Tyrosine Kinase Inhibitor Therapy in an m6A Dependent Manner.
The molecular mechanism of the tyrosine kinase inhibitor (TKI) resistant lung adenocarcinoma is currently unclear, and the role of methylated adenosine at the N6 position in the resistance of cancer stem cells (CSCs) therapy is unknown. This study identified a novel and effective strategy to enhance TKIs therapy response. We first confirmed the sensitization of Metformin enforcing on Osimertinib treatment and revealed the mature miRNAs signatures of the Osimertinib resistant H1975 and HCC827 cells. Let-7b expression was stimulated when adding Metformin and then increasing the therapy sensitivity by decreasing the stem cell groups expanding. Methyltransferase-like 3 (METTL3) increased the pri-Let-7b, decreased both the pre-Let-7b and mature Let-7b, attenuating the Let-7b controlling of stem cell renewal. The addition of Metformin increased the bindings of DNA methyltransferase-3a/b (DNMT3a/b) to the METTL3 promoter. With the help of the readers of NKAP and HNRNPA2B1, the cluster mediated m6A formation on pri-Let-7b processing increased the mature Let-7b, the key player in suppressing Notch signaling and re-captivating Osimertinib treatment. We revealed that the maturation processing signaling stimulated the methylation regulation of the miRNAs, and may determine the stemness control of the therapy resistance. Our findings may open up future drug development, targeting this pathway for lung cancer patients.


[Nature of the interferon circulating in the blood of bronchial asthma patients].
For the elucidation of the nature of interferon circulating in the blood of patients with bronchial asthma in the period of exacerbation the sensitivity of the collected samples to pH 2.0 and 56 degrees C was determined and neutralization test with interferon anti-gamma-serum performed. All the 17 specimens under study were found to contain a mixed population of interferon presented mainly by the gamma-type (greater than or equal to 75%). The remaining amount of interferon (less than or equal to 25%) consisted of alpha- and/or beta-type. The prognostic value of the data obtained is discussed.


Is there a role for pelvic lymph node debulking in advanced cervical cancer?
The purpose of this study is to determine if a survival advantage exists from surgical debulking of enlarged pelvic lymph nodes in advanced cervical cancer. Using information from studies published on the topic of debulking lymph nodes in locally advanced cervical cancer along with baseline control rates of standard treatment and patterns of failure, an estimate of how many patients with bulky pelvic lymph node disease would benefit from this procedure was calculated. The design and feasibility of a randomized trial to test this intervention is also discussed. Based on our calculations 1, 2, and 4% of stage IB, IIB, and IIIB patients, respectively, would benefit from a debulking procedure. Based on our calculations with such small differences in survival along with other inclusion and exclusion criteria, a randomized trial, which would compare chemoradiation to chemoradiation and surgery, would require anywhere from 10,000-30,000 patients per arm. A very small fraction of patients would benefit from a surgical debulking procedure of pelvic nodes. A randomized controlled trial to test this research question is not feasible. A subset population is identified which may benefit from a debulking approach.


Alternative therapies and control for health in cancer and AIDS.
People who are coping with AIDS and many forms of cancer have a sense of being out of control in dealing with their diseases. This stems, to a great degree, from the uncertainty that they feel relative to the accepted medical treatment for their disease. Informants in this naturalistic research study were adamant in their belief that alternative therapies helped them to regain a sense of control over their care and, thus, enhanced their health. It is important that clinical nurse specialists, who often serve as consultants to other nurses, understand and support their patients' choices of therapy. In addition, with evidence to support the benefit of stress reduction on length of survival, advanced practice nurses can play a key role in helping patients reduce stress and, hopefully, effect longevity and quality of life.


Structure and properties of nano-hydroxyapatite/poly(butylene succinate) porous scaffold for bone tissue engineering prepared by using ethanol as porogen.
Biodegradable polymers, because their degradation products are small molecules that do not cause immune system rejection, have been increasingly used by researchers to explore the preparation of scaffold with excellent mechanical properties, biocompatibility and biodegradability. In this study, nano-hydroxyapatite and polybutylene succinate were mixed by solution-blending to prepare a porous scaffold that could be used in the biomedical industry. Based on the viewpoint of bionics, porous scaffold with well pore structure and uniform dispersion of nano-hydroxyapatite particles was prepared using ethanol as a porogen. When ethanol was used as a porogen to prepare the porous scaffold, the effects of different mass ratios of nano-hydroxyapatite and polybutylene succinate on the porosity and pore structure of the porous scaffold were investigated under the same amount of ethanol. The mercury intrusion tests showed that the porosity of the 30 nano-hydroxyapatite/polybutylene succinate porous scaffold was 38.987%. The experiment results of in vitro mineralization and cell culture showed that the porous scaffolds have good osteogenic capacity and cell compatibility, including attachment and proliferation. All experiment results indicated that ethanol can be used as a porogen to prepare nano-hydroxyapatite/polybutylene succinate porous scaffold, and it has great potential as a scaffold for bone tissue engineering.


Establishment of L1210 leukemia cells resistant to the distamycin-A derivative (FCE 24517): characterization and cross-resistance studies.
N-deformyl-N-[4-N,N-bis(2-chloroethylamino)benzoyl] distamycin-A (FCE 24517) is a new cytotoxic anti-tumor agent in phase-1 clinical trials. We have isolated stable FCE-24517-resistant cell sublines from murine leukemia L1210 cells by in vitro exposure to the drug. FCE 24517 selects a mixed population of resistant cells: the L1210/24517(1) cell line in vitro was in fact resistant to the selecting agent (RI 48.3), as well as to L-PAM (RI 5.4) and DX (RI 8.6) and over-expressed the mdr-I gene. When L1210/24517(1) cells were implanted in vivo and evaluated for sensitivity to the same agents, resistance was observed only to FCE 24517 and partially to L-PAM, whereas DX had the same anti-tumor efficacy as on the sensitive line. The clone derived from the above subline (L1210/24517(2)) was resistant to FCE 24517, distamycin-A and other cytotoxic compounds bearing the distamycin-A skeleton, and fully sensitive to DX and other anti-tumor compounds involved in the multi-drug resistance mechanisms, with a complete disappearance of the mdr phenotype. L1210/24517(2) cell line is partially cross-resistant to L-PAM, this resistance being accounted for by higher GSH intracellular levels, which however do not influence the resistance to FCE 24517. In fact, BSO treatment was capable of significantly modifying only the cytotoxicity of L-PAM. Our data suggest that L1210/24517(2) cells present a mechanism of resistance specific for FCE 24517 and related molecules.


MiR-148a modulates HLA-G expression and influences tumor apoptosis in esophageal squamous cell carcinoma.
Esophageal cancer (EC) is a common malignant tumor type, and esophageal squamous cell carcinoma (ESCC) accounts for the majority of EC cases. Previous studies have reported that microRNA (miR)-148a is downregulated in patients with recurrent EC. The human leukocyte antigen-G (HLA-G) is expressed to a high level in primary ESCC tissues and is associated with prognosis. A previous luciferase assay indicated that HLA-G is a target of miR-148a regulation. The aim of the current study was to investigate the expression level of miR-148a in primary ESCC. The regulatory role of miR-148a in HLA-G expression and cell proliferation in ESCC cells was also investigated. The relative expression level of miR-148a was compared between ESCC tumor tissues and adjacent normal tissues. The human ESCC cell line EC9706 was transfected with miR-148a mimic, non-homologous RNA duplex (negative control; NC) or empty vector (blank control; BC). Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to assess the level of HLA-G expression. The cells were stained with Annexin V-fluorescein isothiocyanate/propidium iodide and cell apoptosis was evaluated by flow cytometry. The level of miR-148a expression was significantly lower in primary ESCC tissues compared with adjacent normal tissues (P<0.01). In EC9706 cells transfected with miR-148a mimic, the rate of apoptosis was increased ~13-fold when compared with BC cells (P<0.01). Furthermore, the mRNA level of HLA-G was significantly reduced in cells transfected with miR-148a mimic (P<0.01). The protein levels of HLA-G were also notably decreased. Transfection with non-homologous RNA duplex did not influence the rate of cell apoptosis or expression of HLA-G when compared with the BC group. In conclusion, miR-148a was indicated to be involved in carcinogenesis in primary ESCC through the regulation of HLA-G expression. The current results suggest that miR-148a is a potential biomarker of ESCC.