Coexistence of translocated cytochrome c and nitrated protein in neurons of the rat cerebral cortex after oxygen and glucose deprivation.
Changes in the distribution of immunoreactive cytochrome c and protein nitration were studied in the rat cerebral cortex after oxygen and glucose deprivation by bright field, confocal and electron microscopy. In control cerebral cortex, nitrotyrosine immunoreactivity indicating protein nitration was found mostly in the neuronal nuclear region, with only a small amount distributed in the cytosol, whereas cytochrome c immunoreactivity was found at the inner membrane and in the intermembrane space of the mitochondria. During the recovery phase after oxygen and glucose deprivation, cytochrome c immunoreactivity was released from the intermembrane space of swollen mitochondria into the surrounding cytosol. The cytosol now also displayed nitrotyrosine immunoreactivity, which had diminished in the nuclear region. Both immunoreactivities were dispersed throughout the soma and processes of the cortical neurons. These changes were largely prevented by the administration of cyclosporin A, which inhibits both the mitochondrial permeability transition and the neuronal isoform of nitric oxide synthase while blocking the induction of the inducible isoform. Ischemia/reperfusion injury increases the production of nitric oxide, reactive oxygen species and intracellular factors that damage the mitochondria and liberate apoptotic factors. We suggest that translocation of cytochrome c from the mitochondria to the cytosol, which has been shown to precede the mitochondrial permeability transition, could result from peroxynitrite-mediated nitration. This phenomenon is attenuated by cyclosporin A administration, suggesting a neuroprotective role for this agent.


Endovascular treatment for intracranial vertebrobasilar artery stenosis.
We describe our experience with endovascular treatment for symptomatic intracranial vertebrobasilar artery stenosis. Forty-four patients with intracranial vertebrobasilar artery stenosis (37 vertebral arteries, 7 basilar arteries) were treated with endovascular surgery. Indication criteria for the treatment were (1) medically refractory symptomatic patients; (2) angiographic stenosis of more than 60 %; and (3) short lesion (<15 mm). Under local anesthesia, balloon angioplasty was first performed in all patients. Stenting was performed only in cases with insufficient dilatation, dissection, or restenosis after balloon angioplasty. The degree of stenosis, which was 83 % before treatment, was reduced to 23 % after treatment. The rate of stroke and death within 30 days was 2.3 %. Nine patients (20.5 %) developed restenosis within 6 months. Of these, four patients were symptomatic. All symptomatic patients with restenosis were successfully treated with balloon angioplasty or stenting. Endovascular treatment for vertebrobasilar artery stenoses is feasible and safe in selected patients. Restenosis may be an important cause of recurrent stroke. Therefore, close clinical and neuroradiological follow-ups are essential for patients treated with endovascular surgery to improve long-term results.


SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells.
Glutathione (GSH) is a small-molecule thiol that is abundant in all eukaryotes and has key roles in oxidative metabolism1. Mitochondria, as the major site of oxidative reactions, must maintain sufficient levels of GSH to perform protective and biosynthetic functions2. GSH is synthesized exclusively in the cytosol, yet the molecular machinery involved in mitochondrial GSH import remains unknown. Here, using organellar proteomics and metabolomics approaches, we identify SLC25A39, a mitochondrial membrane carrier of unknown function, as a regulator of GSH transport into mitochondria. Loss of SLC25A39 reduces mitochondrial GSH import and abundance without affecting cellular GSH levels. Cells lacking both SLC25A39 and its paralogue SLC25A40 exhibit defects in the activity and stability of proteins containing iron-sulfur clusters. We find that mitochondrial GSH import is necessary for cell proliferation in vitro and red blood cell development in mice. Heterologous expression of an engineered bifunctional bacterial GSH biosynthetic enzyme (GshF) in mitochondria enables mitochondrial GSH production and ameliorates the metabolic and proliferative defects caused by its depletion. Finally, GSH availability negatively regulates SLC25A39 protein abundance, coupling redox homeostasis to mitochondrial GSH import in mammalian cells. Our work identifies SLC25A39 as an essential and regulated component of the mitochondrial GSH-import machinery.


A diagnostic approach to inflammatory disease of the pancreas by means of endoscopic retrograde cholangio-pancreatography.
Role of ERCP in the diagnosis of inflammatory lesions of the pancreas was evaluated and following conclusions were obtained. 1) Following criteria were considered to be practical for clinical diagnosis of chronic pancreatitis by ERCP; a) More than moderate irregularity or rigidity of margin, dilatation, or irregularity in caliber of PDS, whether extensive or localized, or b) Cyst formation or c) Obstruction of PDS. These criteria permit to diagnose 100% of pancreatolithiasis, 82% of chronic pancreatitis without pancreatolithiasis and 64% of histologically diagnosed chronic pancreatitis but about 13% of "false positive results" must be taken into consideration. 2) ERCP plays an important role in detecting and locating localized or scattered lesions without noticable abnormalities in P-S test. It is also useful in deciding an indication for surgical intervention. However, it has limitations in detecting minimal to moderate pancreatitis. Some of these cases are often picked up by P-S test. 3) Combined approach with ERCP and P-S test is required for diagnosis of inflammatory lesions of the pancreas and either one is incomplete by itself.


Is Overweight Related to the Prognosis of Octogenarians with Lung Cancer?
This study aimed to determine outcomes and prognostic factors associated with octogenarians who underwent pulmonary resection for lung cancer. From 2009 to 2018, 76 octogenarians who underwent pulmonary surgery for lung cancer were enrolled in this study. We divided them into two groups, namely overweight and non-overweight, and investigated their clinicopathological characteristics and outcomes. Disease-specific survival (DSS) rates were determined using Kaplan-Meier curves. Univariate and multivariate analyses were performed to identify prognostic factors. Although perioperative morbidity and mortality in octogenarians were not significantly different between the two groups, the long-term prognosis of the overweight group was significantly worse than that of the non-overweight group. The 3-year DSS rate was 56.5%. The median observation period after surgery was 37.5 (8.9-112.3) months for the entire cohort postoperatively. Kaplan-Meier curves showed that being overweight (body mass index ≥ 25) was associated with worse survival rates in all pathological stages (0 to III) and stage 0/I (DSS, p = 0.036 and p = 0.003, respectively). Multivariate analysis identified overweight as an unfavorable prognostic factor for DSS in patients with stage 0/I lung cancer (hazard ratio 2.240, 95% confidence intervals 1.052-4.564, p = 0.037). Overweight is an independent risk factor, especially in pathological stage 0/I lung cancer. Indications for surgery should be carefully considered in elderly patients with obesity. However, owing to the limitations of this retrospective single-center study, future studies involving multiple institutions are required to confirm our findings.


Prevention of gestational diabetes mellitus in overweight or obese pregnant women: A network meta-analysis.
Several interventions have been implemented to prevent the development of gestational diabetes mellitus (GDM) in obese pregnant women, including physical exercise programs, and administration of metformin, vitamin D and probiotics. The aim of this network meta-analysis was to compare the efficiency of these interventions and identify the optimal. A network meta-analysis of randomized trials was performed comparing the different interventions for the development of GDM in overweight or obese women, either to each other or placebo/no intervention. A search was conducted in four electronic databases and grey literature sources. The primary outcome was the development of GDM; secondary outcomes were other complications of pregnancy. The meta-analysis included 23 studies (4237 participants). None of the interventions was superior compared with placebo/no intervention for the prevention of GDM. Metformin and physical exercise were superior to placebo/no intervention for gestational weight gain (MD -1.21, 95% CI -2.14 to -0.28 and MD -0.96, 95% CI -1.69 to -0.22, respectively). Metformin was superior to placebo/no intervention for caesarean sections and admission to NICU. Interventions aiming to prevent the development of GDM in overweight/obese women are not effective, when applied during pregnancy.


Identification of the kinesin KifC3 as a new player for positioning of peroxisomes and other organelles in mammalian cells.
The attachment of organelles to the cytoskeleton and directed organelle transport is essential for cellular morphology and function. In contrast to other cell organelles like the endoplasmic reticulum or the Golgi apparatus, peroxisomes are evenly distributed in the cytoplasm, which is achieved by binding of peroxisomes to microtubules and their bidirectional transport by the microtubule motor proteins kinesin-1 (Kif5) and cytoplasmic dynein. KifC3, belonging to the group of C-terminal kinesins, has been identified to interact with the human peroxin PEX1 in a yeast two-hybrid screen. We investigated the potential involvement of KifC3 in peroxisomal transport. Interaction of KifC3 and the AAA-protein (ATPase associated with various cellular activities) PEX1 was confirmed by in vivo colocalization and by coimmunoprecipitation from cell lysates. Furthermore, knockdown of KifC3 using RNAi resulted in an increase of cells with perinuclear-clustered peroxisomes, indicating enhanced minus-end directed motility of peroxisomes. The occurrence of this peroxisomal phenotype was cell cycle phase independent, while microtubules were essential for phenotype formation. We conclude that KifC3 may play a regulatory role in minus-end directed peroxisomal transport for example by blocking the motor function of dynein at peroxisomes. Knockdown of KifC3 would then lead to increased minus-end directed peroxisomal transport and cause the observed peroxisomal clustering at the microtubule-organizing center.


Trichomonas vaginalis: analysis of a heat-inducible member of the cytosolic heat-shock-protein 70 multigene family.
A 2253-nucleotide (nt) transcript for a Trichomonas vaginalis heat-shock protein 70, TVCHSP70, has been isolated that encodes for a protein of 659 amino acids with a predicted molecular weight of 71.3 kDa. TVCHSP70 has a short (10-nt) 5' untranslated region (UTR), and the 263-nt 3' UTR is the longest reported for a Trichomonas peptide. Amino-acid sequence analysis and phylogenetic comparison identifies TVCHSP70 as a member of the heat-inducible cytoplasmic HSP70 gene family. Southern-blot data indicate that T. vaginalis contains at least four members of the cytoplasmic HSP70 gene family. Members of the TVCHSP70 family are expressed as 2.3-kb transcripts at low levels during 37 degrees C culture, and their expression is significantly up-regulated at 43 degrees C. Slot-blot analysis of seven T. vaginalis clinical isolates demonstrated a 3- to 44-fold up-regulation of TVCHSP70 under conditions of heat shock (43 degrees C) or oxidative stress (500 microm H2O2) as compared with controls (37 degrees C).


Analytical techniques used to study the degradation of proteins and peptides: physical instability.
The physical instability of proteins and peptides as well as the various analytical techniques used to study the various aspects of physical instability have been reviewed. Physical instability of proteins and peptides involve changes in secondary, tertiary and quaternary structures of these compounds. After a general introduction of the subject the literature data of these changes and their analytical aspects have been summarized in a Table.


Associations Between Acculturation and Weight, Diet Quality, and Physical Activity Among Latina Breast Cancer Survivors: The ¡Mi Vida Saludable! Study.
Among Latinos, greater acculturation to the United States (US) is associated with risk of obesity and obesity-related comorbidities. Less is known about the associations between acculturation and obesity-related modifiable risk factors, such as diet quality and physical activity (PA) among Latina breast cancer survivors. The aim of this study was to explore associations between acculturation and weight status, diet quality, and PA among Latina breast cancer survivors. This is a cross-sectional secondary analysis of baseline data on demographic and clinical characteristics, acculturation, anthropometric measures, diet quality, and PA collected from Latina breast cancer survivors enrolled in the ¡Mi Vida Saludable! (My Healthy Life) behavioral diet and PA intervention trial. Participants were Latina women (n = 167) residing in New York City, with a medical history of stage 0 to III breast cancer, no evidence of recurrent or metastatic disease, and at least 90 days post cancer treatment who participated in the ¡Mi Vida Saludable! randomized controlled trial between July 2016 and October 2018. Acculturation status was measured by the Short Acculturation Scale for Hispanics score, language preference, place of birth, and duration of US residence. Weight, height, and waist and hip circumferences were measured at an in-person clinic visit. Diet information was collected via 3 telephone-based 24-hour dietary recalls and PA information was collected via staff administered 7-day recalls. Linear regression models examined associations between acculturation and weight status, diet quality, and PA. Based on the Short Acculturation Scale for Hispanics acculturation score, more acculturated compared with less acculturated Latinas were younger in age, more educated, and had higher annual household incomes (all, P < .05). Compared with Spanish-speaking Latinas, English-speaking Latinas had larger waist circumference (103 vs 96.1 cm; P = .01) and poorer-quality diets (Healthy Eating Index 2015 scores, 57.3 vs 71.5; P < .001). Greater levels of acculturation were also associated with higher levels of leisure walking at a moderate-to-vigorous intensity (265.8 vs 179.0 min/wk; P =.04). Greater levels of acculturation were associated with higher central obesity and poorer-quality diets. Future lifestyle modification trials tailored to the unique role of acculturation on adopting behavior change recommendations is a promising next step in this line of research.


Associations between diabetes duration and self-stigma development in Japanese people with type 2 diabetes: a secondary analysis of cross-sectional data.
To examine the associations between self-stigma and diabetes duration in a sample of Japanese people with type 2 diabetes. A secondary analysis of a cross-sectional study. Two university hospitals, one general hospital and one clinic in Tokyo, Japan. Outpatients with type 2 diabetes aged 20-74 years and receiving treatment from diabetes specialist physicians (n=209) completed a self-administered questionnaire. Self-stigma was measured as the primary outcome. Patient Activation Measure, body mass index and haemoglobin A1c were measured as secondary outcomes. One-way analysis of covariance showed significant differences in self-stigma levels between the five groups of diabetes duration (≤5 years, 6-10 years, 11-15 years, 16-21 years and 22 years or more) after controlling for age, gender, education, marital status, diabetes treatment (insulin use) and diabetes-related complications, F(4,198)=2.83, p=0.026. Multiple comparisons using Bonferroni correction showed statistically significant differences in self-stigma levels between the groups with ≤5 years (95% CI 59.63 to 69.73) and 11-15 years with diabetes (95% CI 71.12 to 80.82; p=0.020). The highest mean level of self-stigma was observed in the group having diabetes for 11-15 years. Self-stigma was associated with diabetes duration and was lowest after diagnosis and gradually increased, with its highest levels being observed in those having diabetes for 11-15 years. Self-stigma takes time to develop and gradually increases in individuals as it is learnt through direct experiences of diabetes-related stigma after self-administering treatment in everyday social situations.


[Breast cancer].
In Japan, the incidence rate of breast cancer is increasing every year so as to become the most common cancer among Japanese women. One of every 16 women is anticipated to eventually suffer from breast cancer. However, unlike the incidence rate, the mortality rate of breast cancer is low, and the 5-year survival rate is about 80%. Mammography screening has been shown to be effective, but the screening rate is still low(20-30%), compared to screening rates for other organs. To increase the screening rate, the Japanese government has introduced free breast cancer screening. To make the system for breast cancer screening more efficient, we should determine the risk factors for Japanese women, and conduct such screening at public expense.


The effect of bio-converted polyunsaturated fatty acids on the oxidation of TAG containing highly unsaturated fatty acids.
Microbial modification of vegetable fatty acids can often lead to special changes in their structure and in biological function. A bacterial strain, Pseudomonas aeruginosa PR3, is known to carry out multiple hydroxylations on polyunsaturated fatty acids containing 1,4-cis, cis diene structural units, resulting in antibacterial activity. In this paper, in an effort to understand the overall mechanism involved in the varied biological functions of the complicated metabolites of bio-converted polyunsaturated fatty acids, we performed bioconversion of several polyunsaturated fatty acids using PR3, and determined their oxidative activities against fish oil. Bio-converted linoleic acid, eicosapentanoic acid, and docosahexanoic acid promoted effectively oxidation of fish oil. It is assumed that this oxidative effect could plausibly play an important role in the antimicrobial function of these bio-converted fatty acids.


Role of Cl channels in Cl-dependent Na/H exchange.
A novel Na/H exchange activity that requires Cl was recently identified in the apical membrane of crypt cells of the rat distal colon. This study explores the nature of the coupling of Cl and Na/H exchange. A concentration of 100 microM 5-nitro-2-(3-phenylpropylamino)benzoic acid, a Cl channel blocker, inhibited the Cl dependence of both proton gradient-driven 22Na uptake from crypt cell apical membrane vesicles and Na-dependent intracellular pH recovery from an acid load during microperfusion of the crypt lumen. Cl-dependent proton gradient-driven 22Na uptake was inhibited by 94% by 500 microM DIDS but only by 1% by 10 microM DIDS, an anion exchange inhibitor at low concentrations but a Cl channel blocker at high concentrations. In addition, a polyclonal antibody to the cystic fibrosis transmembrane conductance regulator (CFTR) inhibited Cl-dependent proton gradient-driven 22Na uptake by 38%. These results indicate that the Cl dependence of Na/H exchange in the colonic crypt apical membrane involves a Cl channel and not a Cl/anion exchange and permit the speculation that this Cl channel activity represents both CFTR and the outward rectifying Cl conductance.


In Vivo Changes in Dynamic Adjacent Segment Motion 1 Year After One and Two-Level Cervical Arthrodesis.
Biomechanical cadaver testing indicates adjacent segment motion increases after one-level anterior cervical spine arthrodesis, and two-level arthrodesis exacerbates these effects. There is little in vivo evidence to support those biomechanical studies. The purpose of this study was to assess the effects of one- and two-level cervical arthrodesis on adjacent segment motion. Fifty patients received either one-level C56 arthrodesis or two-level C456 or C567 arthrodesis and were tested preoperatively (PRE) and 1 year postoperatively (1YR-POST) along with 23 asymptomatic controls. A validated CT model-based tracking technique was used to measure 3D vertebral motion from biplane radiographs collected during dynamic flexion-extension and axial rotation of the cervical spine. Head and adjacent segment intervertebral end-range range of motion (ROM) and mid-range ROM were compared between one-level and two-level arthrodesis patients and controls. Small (2.3° or less) but non-significant increases in adjacent segment end-range ROM were observed from PRE to 1YR-POST. Mid-range flexion-extension ROM in the C67 motion segment inferior to the arthrodesis and mid-range axial rotation ROM in the C45 motion segment superior to the arthrodesis increased from PRE to 1YR-POST (all p < 0.022). This study provides in vivo evidence that contradicts long-held beliefs that adjacent segment end-range ROM increases appreciably after anterior cervical arthrodesis and that two-level arthrodesis exacerbates these effects. Mid-range ROM appears to be more useful than end-range ROM for detecting early changes in adjacent segment motion after cervical spine arthrodesis.


Comparison of the individual salinity and water deficit stress using water use, yield, and plant parameters in maize.
Though water deficit and salinity effects on plants have similarities, they are physiologically different. This motivated us to separately explore the effects of salinity and water deficit on water consumption, yield, and some plant parameters for maize (Zea mays L., var. SC704). Greenhouse experiments were conducted during two seasons. In one experiment, maize was cultivated in wet soil (matric potential of - 10 kPa), and the irrigation water salinity was varied between treatments (osmotic potentials up to - 336 kPa). In a parallel experiment, five water deficit levels were maintained by irrigating with water to accomplish the same daily water uptake as in the salinity treatments. The experiments were conducted in pots with a randomized design and four replicates. Salinity and water deficit stress significantly affected yield and other plant parameters. However, root dry matter in autumn was not significant. We observed a profound effect of evaporative demand on most of the plant parameters and water use, such as water use efficiency (WUE). For same water use rate, the values of osmotic and matric potential were different. In spring season, the ratios of matric to osmotic potential were 0.25, 0.46, 0.44, and 0.43 in corresponding D1, D2, D3, and D4 water deficit and S1, S2, S3, and S4 salinity treatments. For autumn season, these ratios were 0.26, 0.36, 0.34, and 0.36. We concluded crop models that lump water deficit and salinity (additively or multiplicatively) to predict yields can result in inappropriate predictions.


Thoracoscopic collagen pleurodesis in the treatment of malignant pleural effusions.
Pleurodesis is of a potential benefit in pleural carcinomatosis and symptomatic malignant effusions, but the best way of achieving this is still uncertain. The aim of this prospective study was to analyse the results of pleurodesis after intra-pleural thoracoscopic administration of collagen powder. 45 patients (19 men and 26 women; median age of 64 years, range from 36 to 73 years) with malignant pleural effusions underwent thoracoscopic collagen pleurodesis. The procedure involved thoracoscopic drainage of pleural effusion and intra-pleural insufflation of 1 g of bovine dermal collagen powder under general anaesthesia. Assessment of the immediate side effects and pH estimation of drained pleural fluid took place whilst inpatient. The patients were subsequently followed up for 1 year at 3-monthly intervals including outpatient clinical review and chest radiography. Prognostic value of pleural fluid pH in relation to the outcome of pleurodesis and patients' survival was statistically analysed. The procedure was well tolerated and there were no serious complications or deaths. Thoracoscopic collagen pleurodesis resulted in immediate resolution of malignant pleural effusion and all patients remained free of re-accumulated fluid for at least 1 month. Only 5 (11%) patients later developed recurrent effusion and required its repeat drainage at some point during the follow-up period. In the vast majority (89%) patients, thoracoscopic collagen pleurodesis proved successful in complete and permanent resolution of pleural fluid collection. Acid medium (pH < 7.3) of plural fluid was associated with poor survival (P < 0.05), but did not influence the clinical and radiological outcome of collagen pleurodesis (P > 0.05). Thoracoscopic collagen pleurodesis is a simple and effective method of treatment of malignant pleural effusions.


Comment on: "Pecto-intercostal Fascial Block for perioperative pain management in patients undergoing open cardiac surgery".
This article (Correspondence) is in response to the recently published article on the role of Pecto-intercostal Fascial Block for cardiac procedures by Zhang et al. in "BMC Anesthesiology". I greatly appreciate the authors for publishing this study in which Pecto-intercostal Fascial Block, a novel technique for providing pain relief in open cardiac surgical procedures was evaluated. I wish to present my reflections on this article as well as to add a few more points on this topic.


An intrinsic control element for translational initiation in class 1 integrons.
Integrons are genetic elements able to capture anti-biotic resistance and other genes and to promote their transcription. Here, we have investigated integron-dependent translation of an aminoglycoside 6'-N-acetyltransferase gene (aac(6')-Ib7) inserted at the attI1 site. N-terminal sequencing revealed that translation of this gene was initiated at a GTG codon, which is not part of a plausible translation initiation region (TIR). A short open reading frame (called ORF-11) overlapping the attI1 site was probed by site-directed mutagenesis for its contribution to aac(6')-Ib7 translation. When ORF-11 and its TIR were deleted en bloc, translational efficiency dropped by over 80%, as determined with an acetyltransferase- luciferase fusion product. Invalidation of the ATG start codon of ORF-11 or its putative Shine-Dalgarno sequence resulted in a decrease of over 60%, whereas the decrease was much less pronounced when the amino acid sequence of the putative ORF-11-encoded peptide was altered or when the distance between ORF-11 and aac(6')-Ib7 was doubled. This demonstrates that aac(6')-Ib7 translation is dependent upon the translation of ORF-11, but almost certainly not upon the corresponding peptide. These results lead us to conclude that an intrinsic short ORF present in the 5'-conserved segment of many class 1 integrons may substantially enhance expression at the translational level of captured TIR-deficient anti-biotic resistance genes.


MALDI-TOF "fingerprint" phospholipid mass spectra allow the differentiation between ruminantia and feloideae spermatozoa.
The detailed comparative analysis of sperm lipids could essentially contribute to a better understanding of membrane function in the context of fertilization and, moreover, of sperm preservation. The application of sensitive analytical methods is particularly necessary for endangered species as the available amount of spermatozoa (and, accordingly, extractable lipids) is strongly limited. It will be shown that matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) is a fast, simple and sensitive method for the determination of the phospholipid composition of spermatozoa from several ruminantia (cattle, roe deer, Klipspringer) and feloideae species (domestic cat, Siberian tiger, fosa). Characteristic "fingerprints" are obtained from the positive ion spectra that allow the differentiation between both animal groups. In contrast to the lipid extracts of ruminantia spermatozoa which predominantly contain ether lipids including essential amounts of plasmalogens, the more complex phospholipid composition of feloideae spermatozoa is clearly dominated by diacyl phospholipids and contains only marginal amounts of plasmalogens. It will also be shown that the lipid compositions of ejaculated, electroejaculated and cauda epididymal spermatozoa of the same species are very similar and give comparable data. Therefore, the analysis of ejaculated spermatozoa is not an absolute must.


Can maternal exposure to tamoxifen compromise sperm and behavioural parameters of male rat offspring?
Tamoxifen, a selective non-steroidal estrogen receptor modulator, is the standard adjuvant endocrine treatment for breast cancer. Since information on the risk of using tamoxifen during pregnancy is still scarce, this study evaluated whether the in utero and lactational treatment with this drug could compromise reproductive and behavioural parameters in male offspring. Pregnant Wistar rats were exposed to three doses of tamoxifen (0.12; 0.6; 3 μg/kg), by gavage, from gestational day 15 to lactational day 20. Tamoxifen exposure did not alter the anogenital distance in the male offspring; however, there was a significant increase in the body weight in the 0.12 μg/kg dose and a decrease in the 0.6 μg/kg dose. The male offspring treated with the highest dose exhibited a delay in the onset of puberty, evidenced by an increase in the age of preputial separation. Regarding sperm parameters, there was an increase in the sperm count in the cauda epididymis in the intermediate and highest dose groups, in addition to an increase in the number of static sperm and a decrease in the progressive sperm in the same groups. Moreover, an increase in the number of hyperplasia of the epithelial clear cells was observed in the epididymis. In conclusion, the present study demonstrated that maternal exposure to tamoxifen compromised the installation of puberty of the male offspring and the maturation of the epididymis, affecting sperm storage and motility in the adult life.


Trends in the incidence of in situ and invasive cervical cancer by age group and histological type in Korea from 1993 to 2009.
Our study aims to describe changes in carcinoma in situ (CIS) and invasive cervical carcinoma (ICC) in Korean women diagnosed between 1993 and 2009. All cases of CIS and invasive cervical carcinoma diagnosed from 1993 to 2009 in the Korean National Cancer Incidence database were analyzed. Age-standardized rates (ASRs) and annual percent changes (APCs) in incidence rates were compared according to age and histological type. Additionally, we used Korea National Health and Nutrition Examination Survey (KNHANES) to know the association between screening rate for cervical cancer and incidence rate of cervical cancer. Between 1993 and 2009, 72,240 cases of ICC were reported in Korea. Total incidence rate of ICC was 14.7 per 100,000 females. ASRs of ICC declined 3.8% per year, from 19.3 per 100,000 in 1993 to 10.5 per 100,000 in 2009. Although the overall incidence rate of adenocarcinoma remained stable, invasive squamous cell carcinoma showed a decreasing trend (APC -4.2%). For women aged 60-79 years, ASRs for squamous cell carcinoma increased from 1993 to 2001, and decreased from 2001 to 2009 (APC: -4.6%). Total 62,300 cases of CIS were diagnosed from 1993 to 2009. Total incidence rate of CIS was 12.2 per 100,000 females. ASRs of CIS increased 5.7% per year, from 7.5 per 100,000 in 1993 to 19.0 per 100,000 in 2009. Adenocarcinoma in situ increased 13.2% per year. There was a strong positive correlation between screening rate for cervical cancer and incidence rate for CIS (p-value = 0.03) whereas screening rate showed a strong negative correlation with incidence rate for squamous ICC (p-value = 0.04). The increasing trend in CIS, coupled with a decreasing trend in ICC, suggests the important role of cervix cancer screening. The incidence of adenocarcinoma showed a plateau, but the incidence of adenocarcinoma in situ showed an increasing trend.


Characterization of a cDNA for human glutathione-insulin transhydrogenase (protein-disulfide isomerase/oxidoreductase).
A human liver cDNA expression library in lambda-phage gt11 was screened with monoclonal antibodies to rat liver protein-disulfide isomerase/oxidoreductase (EC 126.96.36.199/22.214.171.124), also known as glutathione-insulin transhydrogenase (GIT). The nucleotide sequence of the largest cDNA insert (hgit-1) was determined. It contained approx. 1500 basepairs, representing an estimated 65% of the glutathione-insulin transhydrogenase message. The amino-acid sequence deduced from this cDNA insert contains a 7-amino-acid long polypeptide determined by sequencing the active-site fragment isolated from the rat GIT protein. A comparison of the nucleotide sequence of hgit-1 and a previously reported nucleotide sequence of rat glutathione-insulin transhydrogenase cDNA shows that the human hgit-1 clone corresponds to the middle of the transhydrogenase message at amino-acid residue number 275 of the rat protein, and codes for 206 amino-acid residues, including one of the two active-site regions of glutathione-insulin transhydrogenase, a stop codon (TAA), a long 3'-noncoding region of over 800 bases, a polyadenylation signal (AATAA), and a 29 base poly(A) tail. There exists high homology between the human and rat enzymes (94% in the overall amino-acid sequence, with 100% in the active site region and 81% in the nucleotide sequence within the coding portion of hgit-1). As with the rat enzyme, the human enzyme shows some identity with another dithiol-disulfide-exchange protein, Escherichia coli thioredoxin. Like rat cDNA, the human hgit-1 cDNA hybridized to rat mRNA of 2500 bases on a Northern blot. The relative quantitative abundance of GIT mRNA in nine rat tissues studied using hgit-1 as a hybridization probe was found to be in the same order as previously found with the rat cDNA. Thus, the above studies indicate that glutathione-insulin transhydrogenase is a highly conserved protein and that the human hgit-1 cDNA is suitable for use as a probe for further studies on gene regulation of this enzyme.


Response of early and late feathering broilers to various stressors.
Growth and responses to potential stressors were measured in early (k+) and late (K) feathering chicks from a common commercial broiler parent stock. Body weights were not different at 3, 10, or 49 days of age with ad libitum feeding, but K/K cockerels were heavier than k+/k+ ones at 24, 38, and 52 days of age with alternate day feeding. No differences in heterophil:lymphocyte ratios were found between K/K and k+/k+ individuals whether they were moved to a new environment or remained in familiar surroundings. Antibody response to sheep erythrocyte antigens was not different in K/w and k+/w pullets. Typical husbandry procedures that might be considered as mild stressors did not elicit physiological stress responses in these meat-type chickens.


Economic evaluation: a comparison of methadone versus buprenorphine for opiate substitution treatment.
The cost of opiate substitution is usually considered lower in cost when methadone is used, as compared to that of buprenorphine, however the overall cost effectiveness of substitution programmes comparing the two drugs remains largely unknown. We evaluated the treatment cost and effectiveness of methadone and buprenorphine when used in an opiate substitution programme in Norfolk, UK. All programme costs, estimated from the perspective of the drug treatment clinic, were collected on 361 opiate-dependent participants over a six-month period. Total costs comprised medication (methadone or buprenorphine) costs, pharmacy supervision and dispensing costs, and drug service clinic costs. Effectiveness was measured in terms of (1) each programmes ability to retain participants in the programme for six months, and (2) the ability of the programme to accomplish complete abstinence from illicit opiate consumption. Overall, mean medication-only costs of methadone were lower than that of buprenorphine, however, pharmacy and clinic costs were lower for the buprenorphine programme. The covariate-adjusted mean total cost of the two programmes was not significantly different. Mean six-month retention rates were higher on the methadone programme, therefore, the methadone programme "dominates" the buprenorphine programme as it was slightly more effective for the same cost. Conversely, when ability to stop taking illicit opiates concomitant with opiate substitution medication was considered, the buprenorphine programme was more effective with an additional cost of £903 per individual who stopped illicit opiate use. The provision of buprenorphine should be considered an appropriate treatment if cessation of illicit opiate use, concomitant with programme retention is considered an important outcome.


Effect of barium meals on gastric electromechanical activity in man. A fluoroscopic-electrogastrographic study.
The relationship between the cutaneously recorded electrogastrogram (EGG) and gastric contractions in man is unclear. We investigated: (1) the relationship between the electrogastrogram (EGG) signals and gastric contractions elicited by barium meals and (2) the effects of barium meals on frequency and amplitude of EGG signals. As documented by fluoroscopy in four healthy subjects, barium meals stimulated three per minute gastric peristalsis which corresponded with simultaneously recorded three cycle per minute (cpm) EGG waves. Eighteen other healthy volunteers ingested 45% (w/v) or 60% barium suspensions. As determined by Fourier analysis, the dominant EGG frequency before barium was 3 cpm in 16 subjects; two subjects had no distinct frequency peaks. After barium ingestion, the mean amplitude or power at 3 cpm and 1 cpm increased, but the increase was significant only after 45% barium. (1) individual EGG waves after barium reflect gastric peristaltic sequences, which are reflected in increases in amplitude or power of 3 cpm EGG activity; (2) density or viscosity of the barium meal affects the gastric myoelectric response; and (3) mechanical correlates of 1 cpm EEG activity are unknown.


Prognosticators of osimertinib treatment outcomes in patients with EGFR-mutant non-small cell lung cancer and leptomeningeal metastasis.
Leptomeningeal metastasis (LM) is a serious complication of non-small cell lung cancer (NSCLC), particularly in patients with EGFR mutations. In this study, we investigated the survival outcomes of patients with EGFR-mutant NSCLC who have developed LM and explored the factors associated with their survival. From April 2018 to November 2021, patients with EGFR-mutant NSCLC who underwent cerebrospinal fluid (CSF) sampling under the clinical suspicion of LM were enrolled. The patients' clinicodemographic characteristics, treatment history including whole-brain radiation therapy (WBRT), overall survival (OS), and intracranial progression-free survival (icPFS) were measured. EGFR mutations in cell-free tumor DNA (ctDNA) of CSF, including T790M mutation, were analyzed. We enrolled 62 patients with NSCLC. The median time form diagnosis to LM was 23.1 months and 16 (25.8%) patients had history of prior third-generation EGFR-TKI use. EGFR mutation in CSF ctDNA was detected in 53 patients (85.5%); of them, 10 (16.1%) had T790M mutation. The patients' icPFS and OS after osimertinib were 6.43 and 9.37 months, respectively, and were comparable among patients with different sensitive EGFR mutations, indicating that EGFR mutation status did not affect osimertinib efficacy. Patients who received WBRT after LM had numerically higher icPFS and OS compared to those without. Multivariate analysis revealed that lack of prior exposure to third-generation EGFR-TKI was associated with better OS. Osimertinib is effective in patients with EGFR-mutant NSCLC who developed LM and prior third-generation EGFR-TKI use was associated with poor survival in these patients. The role of WBRT warrants further investigation.


A comparison of periodontal intraligamental anesthesia using etidocaine HCl and lidocaine HCl.
A double-blind method was used to compare anesthesia duration following intraligamental administration of 1.5% etidocaine with 1:200,000 epinephrine and 2% lidocaine with 1:100,000 epinephrine. Durations of anesthesia in pulpal and soft tissues were monitored following periodontal ligament injections adjacent to the maxillary canines of 20 individuals. Complete pulpal anesthesia was attained in 35% of the teeth injected with etidocaine and in 55% of those receiving lidocaine. Soft tissue anesthesia was consistently achieved. Both pulpal and soft tissue anesthesia were of longer duration following the use of lidocaine solution. These findings suggest that anesthetic duration following periodontal ligament injections is more related to the concentration of vasoconstrictor than to the anesthetic solution employed.


Effects of glyburide on ischemia-induced changes in extracellular potassium and local myocardial activation: a potential new approach to the management of ischemia-induced malignant ventricular arrhythmias.
The increase in extracellular potassium [K+]o levels during the early phase of myocardial ischemia may result in part from activation of adenosine triphosphate-sensitive K+ channels. Glyburide, a second-generation hypoglycemic sulfonylurea, is a potent blocker of these channels. We studied the effects of glyburide on [K+]o and on intramyocardial conduction delay during a 10-minute occlusion of the left anterior descending artery in the dog. K(+)-sensitive electrodes and bipolar plunge electrodes were introduced to record, respectively, [K+]o and local electrograms from close sites in midmyocardial regions in normal, border, and ischemic zones. Recordings were obtained before (control ischemia [CI]) and 20 minutes after intravenous administration of 0.15 mg/kg of glyburide (glyburide plus ischemia [G + I]). During G + I the extent of the increase in [K+]o was less compared to that during CI, and the difference was statistically significant during the first 7 minutes of ischemia in the ischemic zone and during the first 4 minutes of ischemia in the border zone. On the other hand, the degree of local intramyocardial conduction delay was significantly reduced during G + I compared to CI during the entire 10 minutes of ischemia in both the ischemic and border zones. In summary, our results have shown that glyburide significantly reduced the rise of [K+]o and intramyocardial delay during the early phase of acute ischemia and could thus attenuate the electrophysiologic consequences of ischemia that underlie the initial phase of malignant tachyarrhythmias. Although the effects of glyburide may result in part from a direct action of the drug on cardiac adenosine triphosphate-sensitive K+ channels, other metabolic antiischemic effects cannot be ruled out.


Distribution of high density and other lipoproteins in selected LRC prevalence study populations: a brief survey.
Selected lipid and lipoprotein data from the Lipid Research Clinics (LRC) Prevalence Study are presented, with particular emphasis given to high-density lipoprotein (HDL) values. Cross-sectional age- and sex-specific mean values are shown for 7007 white participants in the ten North American LRCs. Comparisons are drawn for males and females (including the pediatric group) and for females using or not using sex hormones. The US-USSR Collaborative Program is summarized, and selected comparisons are noted for the Soviet and United States samples.


An evaluation of the knowledge of the surgical treatment of obesity among surgeons.
Surgical treatment of obesity is currently the only effective treatment option for patients with excess body weight, especially morbid obesity and diseases caused by it. There are no studies evaluating the knowledge of surgeons in the field of bariatric surgery. To assess the knowledge of surgeons regarding bariatric surgery. An anonymous questionnaire was conducted among 143 surgeons in 2010-2011 during local educational conferences. The survey consisted of 10 questions dedicated to the fundamental problems of the surgical treatment of obesity. Theoretical and practical knowledge connected to the so-called "epidemiological awareness" in the surgical treatment of obesity was possessed by 25% of the respondents. Knowledge of surgical techniques is known to most surgeons. Reducing the "oncological risk" after bariatric surgery is known to only 27% of surgeons. Almost 80% of surgeons indicated a necessity of their further education regarding the surgical treatment of obesity. Knowledge of Polish general surgeons in the surgical treatment of obesity is not high, with a high number of surgeons who possess knowledge of the operating technique, whereas only a quarter have a basic knowledge of the indication for surgical treatment. Most surgeons who participated in our study are awaiting educational programmes focused on this issue.


Inflammation: A New Look at an Old Problem.
Pro-inflammatory stress is inherent in any cells that are subject to damage or threat of damage. It is defined by a number of universal components, including oxidative stress, cellular response to DNA damage, unfolded protein response to mitochondrial and endoplasmic reticulum stress, changes in autophagy, inflammasome formation, non-coding RNA response, formation of an inducible network of signaling pathways, and epigenetic changes. The presence of an inducible receptor and secretory phenotype in many cells is the cause of tissue pro-inflammatory stress. The key phenomenon determining the occurrence of a classical inflammatory focus is the microvascular inflammatory response (exudation, leukocyte migration to the alteration zone). This same reaction at the systemic level leads to the development of life-critical systemic inflammation. From this standpoint, we can characterize the common mechanisms of pathologies that differ in their clinical appearance. The division of inflammation into alternative variants has deep evolutionary roots. Evolutionary aspects of inflammation are also described in the review. The aim of the review is to provide theoretical arguments for the need for an up-to-date theory of the relationship between key human pathological processes based on the integrative role of the molecular mechanisms of cellular and tissue pro-inflammatory stress.


Sonographic appearance of intrathyroid ectopic thymus in children.
The aim of this study is to report the common location of intrathyroid ectopic thymus and describe the corresponding sonographic appearances in children. We retrospectively reviewed clinical data and neck or thyroid ultrasonography (US) findings in children from January 2003 to May 2010. Intrathyroid lesions showing hypoechogenicity with multiple linear echogenic branching structures or punctate echogenic foci were considered intrathyroid ectopic thymus. US features of the lesions (location, side, size, and shape) and the indication for US were recorded. A total of 5,414 neck or thyroid US examinations were conducted in 3,195 children. We found 15 lesions that were suspected of being intrathyroid ectopic thymus in 12 patients (0.4%), four boys and eight girls, with a mean age of 6.4 years. The lesions were unilateral in nine patients and bilateral in three patients. All the lesions were located at the mid to lower portion of the thyroid. The long-axis diameter of the lesions ranged from 0.7 to 2.2 cm (mean diameter: 1.5 cm). All lesions had a fusiform shape with well-defined margins. The possibility of intrathyroid ectopic thymus should be considered when a mid- to low-lying intrathyroid lesion with a fusiform shape with multiple linear or punctate internal echoes is detected on US in children.


Treatment of sleep disorders in elderly patients.
Sleep disorders are common among the elderly and are associated with diminished quality of life, increased risk for development of psychiatric disorders, inappropriate use of sleep aids, and decreased daytime functioning. The most common and important sleep disorders in the elderly include insomnia, obstructive sleep apnea syndrome, restless legs syndrome, rapid eye movement sleep behavior disorder, and the advanced sleep phase syndrome. In this article, we summarize the current treatment strategies for each of these sleep-related disorders. Before contemplating specific treatments, the authors recommend that more conservative and nonpharmacologic therapies be attempted first because the elderly are more likely to have medication side effects or complications related to surgery. Many sleep problems can be treated by simple sleep hygiene modifications that can be implemented and adopted easily. For others, therapies that specifically consider older adults may be required. For each of the sleep disorders we provide an updated discussion of therapies beginning with diet and lifestyle, pharmacologic treatment, interventional procedures, surgery, assistive devices, physical and speech therapy, exercise, and emerging therapies with specific considerations for older adults.


The adult horn fly transcriptome and its complement of transcripts encoding cytochrome P450s, glutathione S-transferases, and esterases.
The horn fly, Haematobia irritans, is a blood-feeding parasitic fly with a global distribution that includes Europe, Africa, Asia, and the Americas. The fly has a major detrimental economic impact upon cattle production, with losses estimated at over $800 million annually in the United States and $2.5 billion in Brazil alone. Insecticide resistance in specific horn fly populations has been a problem for many years and there are several mechanisms whereby resistance develops. Little is known about the complement of metabolic enzymes encoded by the horn fly's genome that might provide the fly with detoxification or sequestration pathways to survive insecticide treatments. The cytochrome P450, glutathione S-transferase, and esterase enzyme families contain members that are capable of sequestering and/or detoxifying xenobiotic molecules such as insecticides. We sought to develop a comprehensive dataset of metabolic enzyme-encoding transcript sequences from the adult horn fly, as this is the life stage whose actions directly impose the economic costs to cattle producers. We used an Illumina paired-end read RNA-Seq approach to determine the adult horn fly transcriptomes from laboratory and field populations of horn flies with varying levels of pesticide resistance, including untreated and pyrethroid-treated newly eclosed adult flies. We followed with bioinformatic analyses to discern sequences putatively encoding cytochrome P450, esterase, and GST enzymes. We utilized read-mapping of RNA-Seq data and quantitative real-time polymerase chain reaction (qRT-PCR) to examine gene expression levels of specific P450 transcripts in several fly populations with varying degrees of pesticide resistance.


Utilization of health belief model in comprehending diarrheal disease dynamics: a case of cryptosporidiosis in Uganda.
Diarrheal diseases contribute greatly to the reported global childhood mortality and morbidity with related social, economic consequences. This study was conducted to analyze the utilization of the Health Belief Model (HBM) theory to comprehend diarrheal disease dynamics in Uganda. Our study utilized a qualitative cross-sectional design among adult livestock farmers in selected farming communities. A total of 80 individuals were recruited and interviewed through Focus Discussion Groups (FDGs) (n = 6) and Key Informant Interviews (KIIs) (n = 8) to evaluate diarrheal disease dynamics. The scope of dynamics included but not limited to exposure risks, knowledge, and attitudes. Our results were presented using the five (5) constructs of the HBM. Perceived susceptibility; communities believed that both humans and their animals are at high risk of different kinds of diarrheal infections. The farmers believed that majority of these diarrhea infections are hard to treat especially among animals. Perceived severity; farmers believed that diarrheal diseases are characterized by loss of weight, fever, emaciation, dry eyes, severe prolonged diarrhea and sudden death. Perceived barriers; limited knowledge and misconceptions about the diarrheal infections were great inhibitors to successful disease prevention and control. Self-efficacy; farmers had fear of laxity that interventions being suggested and put in place to curb diarrheal diseases such as cryptosporidiosis would wither away with time thus endemicity of the problem in the community. Modifying factors and cues to action; most of the farmers treat animals by themselves based on; probability, traditional knowledge and previous experience. Sustained public health interventional activities should therefore be undertaken by both human and animal health sectors with maximum community involvement. Communities suggested the need to increase preventive measures and promote household hygiene efforts to always wash hands with soap and running water in order to reduce the burden of diarrhea diseases such as cryptosporidiosis.


Habitat structure, dispersal strategies and queen number in two boreal Leptothorax ants.
In two nearctic ants, Leptothorax canadensis and Leptothorax sp. A, young queens may either found their own nest solitarily after mating or seek adoption into an established colony. Whether a queen disperses or not is associated with genetically determined queen morphology in Leptothorax sp. A. Whereas a majority of winged queens attempt solitary colony founding after mating, most wingless, intermorphic queens return to their maternal nests and new colonies are founded by budding after hibernation. The latter strategy appears to be correlated with patchy, isolated habitats, whereas in extended boreal forests dispersal on the wing is probably more common. Alternative dispersal strategies strongly affect the average number of queens per colony and seasonal fluctuations of colony structure.


Supramolecular aptamer-thrombin linear and branched nanostructures.
Alpha and beta conjugated bis-aptamers against thrombin act as bidentate "glue" for the self-assembly of thrombin nanowires; mixing the bidentate aptamer with a tripodal tridentate alpha aptamer construct yields branched thrombin nanowire structures.


Medical therapy for obesity--current status and future hopes.
In accepting any new drug for the treatment of obesity, the safety profile must make it acceptable for almost everyone. Criteria for selecting treatments involve evaluating the risks to the individual from obesity and balancing that against any possible problems with the treatment. Obesity is a chronic disease that has many causes. Cure is rare and treatment is thus aimed at palliation, that is, producing and maintaining weight loss. Wherever the primary site of action may be, however, the net effect must be a reduction in food intake or an increase in energy expenditure.


Effects of formaldehyde exposure on the extractability of DNA from proteins in the rat nasal mucosa.
Reaction of an homogenate of the rat nasal mucosa with formaldehyde (CH2O) followed by solubilization and extraction in a strongly denaturing aqueous-immiscible organic solvent mixture decreased the quantity of nucleic acids that remained in aqueous solution in comparison with a control homogenate untreated with CH2O. The absent DNA and RNA were located in the interface between the aqueous and organic phases, from which they could be recovered only after enzymatic proteolysis. It is concluded that interfacial nucleic acids were cross-linked to proteins by CH2O. The concentration of cross-links was estimated with 14CH2O; under conditions that rendered 48% of the DNA nonextractable from proteins, there was less than one cross-link per 28,000 nucleotide residues. Exposure of rats to airborne CH2O at concentrations of 0, 2, 6, 15, and 30 ppm (6 hr/day for 2 days) resulted in a statistically significant increase in the percentage of the total DNA from the respiratory mucosa that was located in the interface at concentrations of 6 ppm and higher. However, the percentage of DNA from the olfactory mucosa located in the interface was not increased by CH2O exposure. Analysis of nasal mucosal DNA by ultracentrifugation in CsCl density gradients provided no evidence of a change in the buoyant density of the DNA caused by reaction with CH2O. The results indicate that CH2O may induce DNA-protein cross-links in the respiratory but not in the olfactory mucosa at concentrations equal to or greater than 6 ppm.


Effect of phenobarbital on hepatic cell proliferation and apoptosis in mice deficient in the p50 subunit of NF-kappaB.
Phenobarbital (PB) is a nongenotoxic tumor promoter in the liver. One mechanism by which PB may exert its tumor promoting activity is by inducing oxidative stress. We previously found that PB administration increased hepatic NF-kappaB DNA binding activity. In this study we examined the hypothesis that the effects of PB on cell proliferation and apoptosis are dependent on NF-kappaB. We used a mouse model that is deficient in the p50 subunit of NF-kappaB; previous studies had found that p50-/- mice were less sensitive to the induction of hepatic cell proliferation by PCBs or peroxisome proliferators. Mice (p50-/- and wild-type B6129) were fed a control diet or one containing 0.05% PB for 3, 10 or 34 days. At the end of the experiment, the mice were euthanized and livers removed and processed. PB increased cell proliferation at 3 and 10 days (but not at 34 days), but the deletion of the NF-kappaB p50 subunit did not inhibit these increases. p50-/- Mice had higher cell proliferation at the 3 day (only in mice fed PB) and 34-day timepoints. PB decreased hepatocyte apoptosis after 3 days, slightly decreased it after 10 days, and did not affect it after 34 days. The deletion of the NF-kappaB p50 subunit did not influence PB's effect on apoptosis. In p50-/- mice, apoptosis was increased after 3 or 10 days compared to wild-type mice, but no effect was seen after 34 days. The hepatic expression of the NF-kappaB-regulated gene TNF-alpha correlated more with the hepatic cell proliferation data than with hepatic apoptosis, and was not decreased by the deletion of the p50 subunit. These findings show that the p50 subunit of NF-kappaB is not required for the alteration of hepatocyte proliferation or apoptosis by PB up to 34 days after its administration.


Velocity gradient and contraction frequency of the pyeloureteral system.
An optical detection method, using video imaging, is used to quantitatively record the frequency and velocity profile of the renal pelvis of the rabbit. It is demonstrated that concentric waves originating at the periphery of the pelvis have an initial velocity of 3.2 cm/sec, accelerating toward the pelviureteral junction reaching a final velocity of 6.4 cm/sec.


Hs-CRP and all-cause, cardiovascular, and cancer mortality risk: A meta-analysis.
Inconsistent findings have been reported on the association between high-sensitivity C-reactive protein (hs-CRP) and mortality risk. The objective of this meta-analysis was to investigate the association of elevated baseline hs-CRP levels with all-cause, cardiovascular, and cancer mortality risk in the general population. PubMed and Embase were systematically searched for studies published from inception to October 2016. Prospective observational studies were eligible if they reported the effects of elevated baseline hs-CRP levels on cancer-related, cardiovascular or all-cause mortality in the general population. The pooled adjusted risk ratio (RR) with 95% confidence interval (CI) comparing the highest to the lowest category of hs-CRP levels was used as association measures. A total of 83,995 participants from 14 studies were identified. When comparing the highest to the lowest category of hs-CRP levels, the pooled RR was 1.25 (95% CI 1.13-1.38) for cancer-related mortality, 2.03 (95% CI 1.65-2.50) for cardiovascular mortality, and 1.75 (1.55-1.98) for all-cause mortality, respectively. Subgroup analysis showed that the effect of elevated hs-CRP levels on cancer-related mortality was observed in men (RR 1.26; 95% CI 1.11-1.43) but not in women (RR 1.03; 95% CI 0.83-1.27). Elevated hs-CRP levels can independently predict risk of all-cause, cardiovascular mortality in the general population. However, the gender differences in the predictive role of hs-CRP on cancer mortality should to be further investigated.


Covalent docking in CDOCKER.
Targeted covalent inhibitors (TCIs) are considered to be an important component in the toolbox of drug discovery and about 30% of currently marketed drugs are TCIs. Although these drugs raise concerns about toxicity, their high potencies and prolonged effects result in less-frequent drug dosing and wide therapeutic margins for patients. This leads to increased interests in developing new computational methods to identify novel covalent inhibitors. The implementation of successful in silico docking algorithms have the potential to provide significant savings of time and money in the discovery of lead compounds. In this paper, we describe the implementation and testing of a covalent docking methodology in Rigid CDOCKER and the optimization of the corresponding physics-based scoring function with an additional customizable covalent bond grid potential which represents the free energy change of bond formation between the ligand and the receptor. We optimize the covalent bond grid potential for different common covalent bond formation reaction in TCIs. The average runtime for docking one covalent compound is 15 minutes which is comparable or faster than other well-established covalent docking methods. We demonstrate comparable top rank accuracy compared with other covalent docking algorithms using the pose prediction benchmark dataset for covalent docking algorithms developed by the Keserű group. Finally, we construct a retrospective virtual screening benchmark dataset containing 8 different receptor targets with different covalent bond formation reactions. To our knowledge, this is the largest dataset for benchmarking covalent docking methods. We show that our new covalent docking algorithm has the ability to identify lead compounds among a large chemical space. The largest AUC value is 0.909 for the target receptor CATK and the warhead chemistry of the covalent inhibitors is addition to the aldehyde functionality.


Endothelial cell seeding influences lesion development following arterial injury in the cholesterol-fed rabbit.
A functionally intact endothelial monolayer is thought to be critical for the adaptive process of vascular remodeling. This study was undertaken to examine the hypothesis that endothelial restoration is a critical determinant of remodeling after balloon angioplasty. Rabbits (N=12) were fed a cholesterol-supplemented diet (0.5%) and were subjected to bilateral balloon catheter injury of the iliofemoral arteries. At the time of injury, autologous venous endothelial cells (ECs) were implanted on one artery; the contralateral vessel served as control. A mean of 42 days after injury, arteriography was performed, followed by vessel harvest and histologic analysis. High grade (> or =70%) stenoses or occlusion were present in 55% of control and none of the EC-seeded arteries. EC-seeding was associated with improved mean (1.0 +/- 0 vs. 0.7 +/- 0.1, P<0.001) and minimal (0.7 +/- 0.1 vs. 0.4 +/- 0.1, P<0.001) luminal diameters by angiography. Seeded arteries demonstrated decreased medial area (0.69 +/- 0.04 vs. 1.04 +/- 0.09 mm(2), P<0.001), a more uniform range of final lumen area (P<0.0001), and a positive remodeling index. Neointimal area was not significantly different. Stenoses were characterized primarily by larger neointimal area (2.02 +/- 0.18 vs. 1.38 +/- 0.09 mm(2), stenotic vs. non-stenotic, P<0.005). Final lumen area was strongly influenced by both neointimal growth and vessel remodeling. These data support the concept that endothelial restoration is a critical determinant of the outcome of vessel wall repair, particularly in the context of hypercholesterolemia.


Magnetic resonance imaging-based finite element stress analysis after linear repair of left ventricular aneurysm.
Linear repair of left ventricular aneurysm has been performed with mixed clinical results. By using finite element analysis, this study evaluated the effect of this procedure on end-systolic stress. Nine sheep underwent myocardial infarction and aneurysm repair with a linear repair (13.4 +/- 2.3 weeks postmyocardial infarction). Satisfactory magnetic resonance imaging examinations were obtained in 6 sheep (6.6 +/- 0.5 weeks postrepair). Finite element models were constructed from in vivo magnetic resonance imaging-based cardiac geometry and postmortem measurement of myofiber helix angles using diffusion tensor magnetic resonance imaging. Material properties were iteratively determined by comparing the finite element model output with systolic tagged magnetic resonance imaging strain measurements. At the mid-wall, fiber stress in the border zone decreased by 39% (sham = 32.5 +/- 2.5 kPa, repair = 19.7 +/- 3.6 kPa, P = .001) to the level of remote regions after repair. In the septum, however, border zone fiber stress remained high (sham = 31.3 +/- 5.4 kPa, repair = 23.8 +/- 5.8 kPa, P = .29). Cross-fiber stress at the mid-wall decreased by 41% (sham = 13.0 +/- 1.5 kPa, repair = 7.7 +/- 2.1 kPa, P = .01), but cross-fiber stress in the un-excluded septal infarct was 75% higher in the border zone than remote regions (remote = 5.9 +/- 1.9 kPa, border zone = 10.3 +/- 3.6 kPa, P < .01). However, end-diastolic fiber and cross-fiber stress were not reduced in the remote myocardium after plication. With the exception of the retained septal infarct, end-systolic stress is reduced in all areas of the left ventricle after infarct plication. Consequently, we expect the primary positive effect of infarct plication to be in the infarct border zone. However, the amount of stress reduction necessary to halt or reverse nonischemic infarct extension in the infarct border zone and eccentric hypertrophy in the remote myocardium is unknown.


[Description of the use of inhaled rescue medication in an asthmatic population treated in the Primary Care clinics. UMI-ASMA Study].
To describe the quantitative use of inhaled rescue medication in an asthmatic population treated in the Primary Care clinics, and secondly to determine its possible relationship as regards other variables associated with control. An observational, descriptive study was conducted on a randomised sample of all the asthmatic patients with more than one year of onset, and coming from 17 Primary Care catchment areas. 1 year observation period. The data collected included sociodemographic variables and characteristics of the asthma, such as the use of short-acting beta-agonists (SABA) and level of control as regards its frequency of use, the use of inhaled control medication (ICM), number of hospital exacerbations, smoking habits, and availability of an action plan. The data were obtained from the clinical history and the computerised prescription modules. A total of 442 asthmatic patients were included (59.5% female), with a mean age of 45.4 years. The total number of SABA containers prescribed in one year per patient was between 0 and 25 containers, with a mean of 4.26 (SD=4.1). Only 46.6% showed a regular use of an ICM. The number of SABA containers prescribed to patients with an intermittent use of an ICM was significantly higher than those patients that used it regularly (P=.001). There was an association between the number of exacerbations and the number of SABA containers prescribed (Spearman correlation coefficient=0.474, P<.001), as such that the higher the number of containers prescribed there was also a higher number of hospitalised asthmatic exacerbations. A considerable number of asthmatics in the sample had elevated prescriptions for SABA inhalers and within the defined quantitative ranges of at least a partially or poor-controlled asthma. There is a positive relationship between the overuse of SABA and the intermittent use of the ICM, the same as with hospital exacerbations, smoking, and the lack of a written action plan..


Activity of tachykinin NK1 and bradykinin B2 receptor antagonists, and an opioid ligand at different stimulation parameters in neurogenic inflammation in the rat.
Stimulation of the saphenous nerve in the anaesthetised rat results in cutaneous neurogenic oedema formation. We have examined the effect of a tachykinin NK1 and a bradykinin B2 antagonist, and a mu-opioid agonist on plasma extravasation observed in response to two differing nerve stimulating parameters (10 V, 1 ms, 2 Hz and 25 V, 2 ms, 10 Hz). The NK1 antagonist SR140333 abolished oedema, supporting the theory that an NK1 agonist is a primary mediator of neurogenic oedema. The B2 antagonist HOE 140 had no effect, indicating a lack of involvement of B2 receptors in this response. The pre-junctionally acting mu-opioid agonist DAMGO significantly inhibited oedema formation at the 10 V, 1 ms, 2 Hz (P < 0.001), but not the 25 V, 2 ms, 10 Hz stimulation parameters. Thus a post-junctionally acting NK1 antagonist inhibited neurogenic oedema formation induced by both stimulation parameters, whilst a pre-junctionally acting mu-opioid agonist acted only at 10 V, 1 ms, 2 Hz parameters. These findings could be of interest with respect to therapeutic approaches of pathophysiological conditions which involve a neurogenic component.


Acid glycohydrolase in Chinese hamster (Cricetulus griseus) with spontaneous diabetes--V. Subcellular distribution in the kidney.
1. Seven renal glycohydrolases were measured in four subcellular fractions prepared from highly inbred aglycosuric (AV-line) and glycosuric (XA-line) Chinese hamsters. 2. alpha-D-galactosidase and beta-D-galactosidase were highest in the nuclear (N) and supernatant (S) fractions; both fractions showed reduced activities in the XA animals. 3. alpha-D-mannosidase was chiefly a particulate enzyme and its decrease in XA animals was evident in N, lysosomal-mitochondrial (LM) and mitochondrial-microsomal (MM) fractions. 4. No significant difference in N-acetyl-beta-D-glucosaminidase was found in any of these subcellular fractions between AV and XA animals. 5. Although total alpha-L-fucosidase and beta-D-fucosidase levels were similar in AV and XA kidneys, a difference was observed in the S fraction. 6. beta-D-glucuronidase was virtually absent in N and LM fractions and the S fraction of AV kidneys showed higher activity than the XAs.


CAPD with an amino acid dialysis solution: a long-term, cross-over study.
This prospective cross-over study was undertaken to evaluate the safety and efficacy of a 1% amino acid dialysis solution on the nutritional and metabolic changes, plasma amino acid profiles and peritoneal membrane function of patients on CAPD. Six CAPD patients had one exchange a day with two liters of this solution over a six month period. Every month there was a medical examination, anthropometric measurements and dietary inquiry were made, blood biochemistry tests were done. Every three months renal function, peritoneal function, aminograms of plasma and dialysate and nitrogen balance were determined. Data were compared with those obtained one month prior to and three months after withdrawal of amino acid administration. Nitrogen balance, which was negative (-1.3 g/day) became positive (+3.1 g/day). Patients who were already overweight increased in weight, both in fat and lean mass. Plasma cholesterol and triglycerides significantly decreased and the amino acid profile moved towards normal; plasma urea levels increased and pH and bicarbonate decreased slightly but significantly (P less than 0.05). Plasma protein concentrations did not change. All the above parameters turned towards basal values when amino acids were discontinued. We conclude that amino acids can be used as osmotic agents for CAPD since they do not cause toxic effects or impair peritoneal membrane function. Moreover, they can help the nutritional status, provided that an increase in weight is prevented and the slight worsening of systemic acidosis is corrected.


Detection of infectious bursal disease virus (IBDV) genome in free-living pigeon and guinea fowl in Africa suggests involvement of wild birds in the epidemiology of IBDV.
Infectious bursal disease (IBD) virus (IBDV) serotype 1 is the causative agent of IBD, a highly contagious immunosuppressive disease of young chickens. In this study, we examined IBDV infection in apparently healthy 21 guinea fowls and 20 pigeons obtained in Tanzania and Zambia by virus neutralization test (VNT) and reverse transcription polymerase chain reaction (RT-PCR) for the VP2 hypervariable region (VP2-HVR) of IBDV. Two guinea fowls (9.5%) in Tanzania were RT-PCR and VNT positive for IBDV, and 1 pigeon (5%) in Tanzania was RT-PCR positive and VNT negative. Phylogenetic analysis based on the nucleotide sequences of the PCR products indicated that segment A of IBDV detected from one guinea fowl and a pigeon belonged to the very virulent genotype of European/Asian type, while the other IBDV detected from a guinea fowl belonged to the classical genotype. To our knowledge, this is the first report of detection of the IBDV genome in free-living pigeons and guinea fowls. The detection of IBDV from apparently healthy guinea fowls and pigeons elucidates the role of wild birds in the epidemiology of IBDV.


The number of metastatic lymph nodes: a promising prognostic determinant for gastric carcinoma in the latest edition of the TNM classification.
The number of metastatic regional lymph nodes determines the new pN categories in the 5th edition of the TNM classification. Our retrospective study was conducted to compare the new method of defining lymph node status with the conventional classification, consisting of the anatomic extent of lymph node metastases, a well-established prognostic factor. The study was based on clinical data for 493 patients with gastric carcinomas who underwent potentially curative operations and had histologically confirmed nodal metastases. These patients were stratified into 1) n categories according to the Japanese Classification of Gastric Carcinoma, 2) the new pN categories, and 3) the pN categories determined by the number of metastatic perigastric nodes resected by standard D1 gastrectomy. Survival data were analyzed for each group. The number of metastatic nodes after D2 lymphadenectomy reflected prognosis well and was shown by multivariate analysis to be a strong independent prognostic factor. When the classification was performed limited to the metastatic perigastric nodes, stage migration was evident, but the variable remained competent as a prognostic indicator. The number of metastatic nodes is a promising determinant in the new international stage classification.


Convergence of techniques for the evaluation of discrepant data.
The problem of evaluating discrepant data has been addressed by several authors over the previous 20 yr. More recently some attention has been given to the use of the median, which is expected to have better statistical 'robustness'. The various evaluation techniques should converge towards the 'true' value as the number of data in a data set increases, and the 'robustness' of each evaluation technique can then be tested by the rate at which that technique converges. Several evaluation techniques have been applied to discrepant data sets, and the results are shown to converge as the size of the data set grows. The discrepant data sets used as examples are the measured half-lives of 90Sr and 137Cs. Differences in the behaviour of the evaluation techniques are discussed, as applied to these data sets. The half-lives deduced from this study are: 90Sr 10,551+/-14 days; 137Cs 10,981+/-11 days.


Titanium levels in the organs and blood of rats with a titanium implant, in the absence of wear, as determined by double-focusing ICP-MS.
Titanium (Ti) has long been regarded as an inert and biocompatible metal, ideal for biomedical applications such as dental implants or joint replacements. However, concerns about the biocompatibility of Ti have lately arisen. Unfortunately, information on reliable Ti baseline physiological levels in blood and organ tissues is still pending and the real effects of physiological corrosion as opposed to wear processes of Ti or Ti alloys implants is controversial so far. In this work a previously developed and validated methodology, based on using double-focusing inductively coupled plasma mass spectrometry (DF-ICP-MS) has been used to establish Ti basal levels in blood and organs (heart, liver, spleen, kidneys, and lungs) of Wistar rats. These data were compared with the levels found in three Wistar rats implanted with a Ti wire embedded in their femur for 18 months, in order to assign possible Ti released purely due to non-wear physiological mechanisms. Results showed that Ti content in all the selected organ tissues and blood was higher than previously determined Ti basal levels, clearly showing both corrosion of the Ti implant and systemic Ti accumulation in target tissues. These results indicate that Ti metal corrosion occurs. This seems to be the only mechanism responsible in the long term for the observed passive dissolution of Ti of the implant in the absence of wear. A comparative study of the systemic distribution of the soluble and particulate Ti potentially released from Ti implants was also carried out by intraperitoneally injection of soluble Ti(citrate)(3) and insoluble TiO(2) particles, respectively. Different systemic Ti storage was observed. Whereas soluble Ti was rapidly transported to all distal organs under study, TiO(2) particles were only accumulated in lung tissue.


Essential embryonic roles of the CKI-1 cyclin-dependent kinase inhibitor in cell-cycle exit and morphogenesis in C elegans.
Following a phase of rapid proliferation, cells in developing embryos must decide when to cease division and then whether to survive and differentiate or instead undergo programmed death. In screens for genes that regulate embryonic patterning of the endoderm in Caenorhabditis elegans, we identified overlapping chromosomal deletions that define a gene required for these decisions. These deletions result in embryonic hyperplasia in multiple somatic tissues, excessive numbers of cell corpses, and profound defects in morphogenesis and differentiation. However, cell-cycle arrest of the germline is unaffected. Cell lineage analysis of these mutants revealed that cells that normally stop dividing earlier than their close relatives instead undergo an extra round of division. These deletions define a genomic region that includes cki-1 and cki-2, adjacent genes encoding members of the Cip/Kip family of cyclin-dependent kinase inhibitors. cki-1 alone can rescue the cell proliferation, programmed cell death, and differentiation and morphogenesis defects observed in these mutants. In contrast, cki-2 is not capable of significantly rescuing these phenotypes. RNA interference of cki-1 leads to embryonic lethality with phenotypes similar to, or more severe than, the deletion mutants. cki-1 and -2 gene reporters show distinct expression patterns; while both are expressed at around the time that embryonic cells exit the cell cycle, cki-2 also shows marked expression starting early in embryogenesis, when rapid cell division occurs. Our findings demonstrate that cki-1 activity plays an essential role in embryonic cell cycle arrest, differentiation and morphogenesis, and suggest that it may be required to suppress programmed cell death or engulfment of cell corpses.


Alanyl-PNA homoduplex: A-T pairing with the N7-regioisomer of adenine.
The N7-regioisomer of adeninyl alanine can be used as a building block for the synthesis of alanyl-PNA. By changing the nucleobase connectivity from N9 to N7, pairing with the Hoogsteen side is no longer possible and the order of donor/acceptor positions at the Watson-Crick side is reversed. This influences the pairing selectivity but not the stability of alanyl-PNA self-pairing complexes, as shown by UV and CD spectroscopy.


Sodium cromoglycate therapy in IgA nephropathy: a preliminary short-term trial.
Sodium cromoglycate (SCG), an antiallergic agent, is an effective drug in an experimental model for IgA nephropathy. The present report concerns a preliminary trial of patients with IgA nephropathy and proteinuria (greater than 1.0 g/d), which was conducted to determine the therapeutic value of SCG. Thirty patients were divided into two groups: one group (n = 15) was given oral SCG (1,200 mg/d) for 16 weeks after an observation of 4 weeks (SCG group), and the other group (n = 15) was observed without the changes of prescription (control group). No fluctuations were noted in proteinuria during the observation period in both groups. Proteinuria in the SCG group slowly decreased throughout the time course; however, a significant reduction was observed at 16 weeks as compared with that of the control group. On the other hand, no significant changes were noted in creatinine clearance (Ccr), serum albumin (s-alb), serum IgA (s-IgA), and IgA-CIC between groups. Five of 15 patients, designated "responders", showed a reduction in proteinuria of more than 50% of the pre-value (average value of observations period). The responder and nonresponder groups were comparable in clinical and histopathological data at the beginning of the trial. Nevertheless, no significant correlations arose concerning any point. Short-term SCG therapy may be beneficial in reducing proteinuria in some patients with IgA nephropathy. Allergic reactions may participate in the pathogenesis of this disease.


The cobra complement system: I. The alternative pathway of activation.
The complement system of the cobra snake is of particular interest because cobra venom contains cobra venom factor (CVF), a protein that is related to C3 and forms a stable C3 convertase with mammalian Factor B. We investigated the alternative pathway of cobra complement. Cobra plasma lysed erythrocytes in presence of Mg-EGTA of some mammalian species, but not cobra erythrocytes. The hemolytic activity was inhibited by EDTA and destroyed by heating. Preincubation of cobra plasma with alternative pathway activators (zymosan, inulin, lipopolysaccharide), with small nucleophiles (methylamine, hydrazine), or with chaotropes (KSCN) abrogated the hemolytic activity. The activity of cobra plasma was not affected by CVF. Cobra plasma also lysed EAC1423 cells in presence of EDTA but not EAC142 cells (prepared with sheep erythrocytes, rabbit antibody, and human complement proteins) indicating the presence of C5 in cobra plasma that is susceptible to activation by the human C5 convertase. These results indicate that the cobra has a complement system with an alternative pathway very similar to mammalian complement.


Pancreatoblastoma associated with incomplete Beckwith-Wiedemann syndrome: case report and review of the literature.
A case of pancreatoblastoma (PB) in a 2 month-old male infant with incomplete Beckwith-Wiedemann syndrome is presented. Clinical examination disclosed left hemihypertrophy, macroglossia, bilateral exophthalmos, and enlargement of the left testis. Imaging with ultrasound and computed tomography scan showed a well-defined, heterogeneous, and grossly cystic mass arising from the head of the pancreas. Serum alpha-fetoprotein (AFP) level was elevated. The tumor was completely resected, and the histological analysis showed PB. The patient's recovery was uneventful, and AFP returned to normal values after surgery. The child has been disease-free for 5 years, and his serum AFP remained within normal values. Six other examples of this association, PB, and Beckwith-Wiedemann syndrome are recorded in the literature. The risk of developing tumor in this syndrome (complete and incomplete form) increases when hemihypertrophy is present, and the need for routine screening examination is warranted. Beckwith-Wiedemann syndrome was suggested to be a favorable biological marker for survival in children who have intraabdominal tumors.


Adjustment formulae to improve the correlation of white-to-white measurement with direct measurement of the ciliary sulcus diameter by ultrasound biomicroscopy.
This study evaluates the correlation between horizontal white-to-white (WTW) distance using Caliper and Orbscan IIz with the ciliary sulcus diameter measured by high frequency ultrasound biomicroscopy (UBM) and presents an adjustment formula to improve the correlation. We measured horizontal sulcus-to-sulcus (STS) dimension of 273 right eyes of 273 high myopic patients with 35 MHz UBM and horizontal WTW using Orbscan IIz and Caliper. Mean WTW diameter, differences, and the correlation of measurement methods were evaluated. The mean spherical equivalent was -8.79 ± 4.87 diopters. Mean horizontal STS dimension with UBM was 12.13 ± 0.45 mm (range, 10.81-13.42 mm). Mean WTW diameter in the Caliper method was 11.70 ± 0.40 mm (range, 10.6-12.8 mm) and 11.70 ± 0.40 mm (range, 10.5-13.1 mm) in the Orbscan method. Mean difference of UBM STS and WTW with Caliper was 0.48 ± 0.28 mm (range, -0.19 to 1.37 mm). Mean difference of UBM STS diameter and Orbscan WTW was 0.38 ± 0.31 mm (range, -0.64 to 1.29 mm). The Pearson correlations of WTW diameter measured by Caliper and Orbscan with UBM's STS diameter were 0.778 and 0.773, respectively. This difference diminished after adjustment. The 95% limit of agreement was almost the same in Caliper and Orbscan (-0.07 to 1.03 compared with -0.23 to 0.99). There is a significant difference in measurements between STS diameter using UBM and WTW diameter utilizing Caliper and Orbscan. This difference diminished after our recommended adjustment.


Growth inhibition of transplantable murine colon adenocarcinoma 38 by indomethacin.
The anti-inflammatory drug indomethacin was tested for antitumor activity against transplantable mouse colon adenocarcinoma 38 (colon 38). Groups of BDF1 mice (C57BL/6 X DBA/2) were given intraperitoneal injections of this drug beginning on the 6th day after subcutaneous implantation of the tumor and continued for 4 to 8 days. In other groups of mice, identical treatment was delayed until the 16th day after implantation of the tumor. The higher antitumor activity against colon 38 was obtained with earlier initiation of treatment, indicated by decreased growth of the tumor and increased life span of the host. The later initiation of the treatment produced less antitumor activity. The antitumor activity was, however, less than that of 5-fluorouracil, which was used as a positive control drug. The two drugs in combination produced few advantages over 5-fluorouracil alone using the dose schedule designed in the present experiment. Indomethacin treatment significantly reduced prostaglandin E and F levels in the tumor tissue, but 5-fluorouracil did not. It seems likely that the inhibition of prostaglandin biosynthesis by indomethacin underlies the antitumor effect of this drug on colon 38.


The effect of pretreatment with Corynebacterium parvum on the growth of a chemical induced transplanted murine tumor.
Unspecific immunostimulation with or without specific tumor immunotherapy may well contribute to the control of minimal residual cancer. Corynebacterium parvum (C.p.) has been shown to raise the level of immunocompetence in tumor bearing animals. Experiments are reported, which aim at an evaluation of optimal conditions for an immunostimulation with C.p. prior to the transplantation of BALB/c Meth A ascitis. Using different dosages, routes of injection and schedules of vaccination it was found, that the highest non-toxic dose of C.p. per mouse yielded the optimal inhibition of tumor growth, the longest survival of tumor bearing hosts and the highest number of tumor rejections as compared to untreated controls. If the vaccine was distributed to at least 4 sites of injection, the s.c. route appeared superior to i.p. application. The intravenous route appeared to be most effective. The oral route seemed to inhibit tumor growth, if not less than 4 mg/mouse were fed daily for five days. The mechanism of action of C.p. in the model system used is discussed and correlated with an appropriate timing of both C.p. sensitization and tumor challenge.


Children's Everyday Learning by Assuming Responsibility for Others: Indigenous Practices as a Cultural Heritage Across Generations.
This chapter uses a comparative approach to examine the maintenance of Indigenous practices related with Learning by Observing and Pitching In in two generations--parent generation and current child generation--in a Central Mexican Nahua community. In spite of cultural changes and the increase of Western schooling experience, these practices persist, to different degrees, as a Nahua cultural heritage with close historical relations to the key value of cuidado (stewardship). The chapter explores how children learn the value of cuidado in a variety of everyday activities, which include assuming responsibility in many social situations, primarily in cultivating corn, raising and protecting domestic animals, health practices, and participating in family ceremonial life. The chapter focuses on three main points: (1) Cuidado (assuming responsibility for), in the Nahua socio-cultural context, refers to the concepts of protection and "raising" as well as fostering other beings, whether humans, plants, or animals, to reach their potential and fulfill their development. (2) Children learn cuidado by contributing to family endeavors: They develop attention and self-motivation; they are capable of responsible actions; and they are able to transform participation to achieve the status of a competent member of local society. (3) This collaborative participation allows children to continue the cultural tradition and to preserve a Nahua heritage at a deeper level in a community in which Nahuatl language and dress have disappeared, and people do not identify themselves as Indigenous.


Derivation and validation of clinical phenotypes for COPD: a systematic review.
The traditional classification of COPD, which relies solely on spirometry, fails to account for the complexity and heterogeneity of the disease. Phenotyping is a method that attempts to derive a single or combination of disease attributes that are associated with clinically meaningful outcomes. Deriving phenotypes entails the use of cluster analyses, and helps individualize patient management by identifying groups of individuals with similar characteristics. We aimed to systematically review the literature for studies that had derived such phenotypes using unsupervised methods. Two independent reviewers systematically searched multiple databases for studies that performed validated statistical analyses, free of definitive pre-determined hypotheses, to derive phenotypes among patients with COPD. Data were extracted independently. 9156 citations were retrieved, of which, 8 studies were included. The number of subjects ranged from 213 to 1543. Most studies appeared to be biased: patients were more likely males, with severe disease, and recruited in tertiary care settings. Statistical methods used to derive phenotypes varied by study. The number of phenotypes identified ranged from 2 to 5. Two phenotypes, with poor longitudinal health outcomes, were common across multiple studies: young patients with severe respiratory disease, few cardiovascular co-morbidities, poor nutritional status and poor health status, and a phenotype of older patients with moderate respiratory disease, obesity, cardiovascular and metabolic co-morbidities. The recognition that two phenotypes of COPD were often reported may have clinical implications for altering the course of the disease. This review also provided important information on limitations of phenotype studies in COPD and the need for improvement in future studies.


Ictal Symmetric Tonic Extension Posturing and Postictal Generalized EEG Suppression Arising From Sleep in Children With Epilepsy.
The identification of a biomarker for sudden unexpected death in epilepsy (SUDEP) has the potential to save lives. Generalized convulsive seizures and postictal generalized suppression on electroencephalography (EEG) most often precede sudden unexpected death in epilepsy (SUDEP) and are potential biomarkers. We identify the EEG and seizure characteristics associated with postictal generalized EEG suppression in children with epilepsy. Video EEGs were reviewed for seizure type, duration and semiology, and electrographic features. To identify predictors of postictal generalized EEG suppression, we identified 40 children with generalized convulsive seizures from a group of 399 patients who experienced an electroclinical seizure during video-EEG. Seventy-seven generalized convulsive seizures with and without postictal generalized EEG suppression were anayzed. Age of seizure onset was older in 19 children with postictal generalized EEG suppression (mean 6.8 years old, 95% CI [4.7-8.9]) than in 21 without postictal generalized EEG suppression (3.0 years old, [1.1-4.1], P = 0.041). Postictal generalized EEG suppression occurred significantly more often from sleep than awake (point of estimate 16.67; 95% CI [0.97-32.36], P < 0.038). Shorter duration of the clonic phase (-0.76; [-1.338, -0.133], P = 0.018) was significantly associated with postictal generalized EEG suppression. Ictal symmetric tonic extension posturing significantly increased the odds of postictal generalized EEG suppression (42.94; [18.77, 67.12], P = 0.001). All 15 generalized convulsive seizures with a terminal burst-suppression pattern were followed by postictal generalized EEG suppression in contrast to 19 of 62 generalized convulsive seizures without burst-suppression (15.32, P < 0.001). Ictal decerebrate-like symmetric tonic extension posturing with shorter clonic phase and a terminal burst-suppression pattern identify malignant generalized convulsive seizures, associated with postictal generalized EEG suppression and a potentially increased risk of sudden unexpected death in epilepsy.


Segregation distortion of X-linked marker genes in interspecific crosses between Mus musculus and M. spretus.
An interspecific cross was made between females of the C3H/HeHa.Pgk-1 a inbred laboratory strain of Mus musculus and males of the separate species Mus spretus. The F1 males are sterile but the F1 females are fertile and they were backcrossed to both C3H and spretus males. Evidence is presented from the segregation of X-linked marker genes that the interspecific F1 female has a genetically deleterious effect on the C3H X chromosome that is expressed as a male-lethal effect with the spretus Y chromosome but not with the musculus Y chromosome of C3H.


A tumor-to-lymph procedure navigated versatile gel system for combinatorial therapy against tumor recurrence and metastasis.
Application of cancer vaccines is limited due to their systemic immunotoxicity and inability to satisfy all the steps, including loading of tumor antigens, draining of antigens to lymph nodes (LNs), internalization of antigens by dendritic cells (DCs), DC maturation, and cross-presentation of antigens for T cell activation. Here, we present a combinatorial therapy, based on a α-cyclodextrin (CD)-based gel system, DOX/ICG/CpG-P-ss-M/CD, fabricated by encapsulating doxorubicin (DOX) and the photothermal agent indocyanine green (ICG). Upon irradiation, the gel system exhibited heat-responsive release of DOX and vaccine-like nanoparticles, CpG-P-ss-M, along with chemotherapy- and phototherapy-generated abundant tumor-specific antigen storage in situ. The released CpG-P-ss-M acted as a carrier adsorbed and delivered antigens to LNs, promoting the uptake of antigens by DCs and DC maturation. Notably, combined with PD-L1 blocking, the therapy effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis.


In vitro digestibility of different prey species of minke whales (Balaenoptera acutorostrata).
Information on diet composition, daily energy expenditure, energy storage and the utilization of energy in the prey are important factors when evaluating the food consumption of minke whales (Balaenoptera acutorostrata) during their summer stay in northern waters. The purpose of the present study was in this context to obtain information on the digestible energy (DE) of different prey selected by minke whales. An in vitro three-stage digestion technique, simulating the different compartments of the digestive system, has been developed. The initial step simulated the anaerobic microbial fermentation of substrate in the forestomach. The next stage included the addition of pepsin (EC 220.127.116.11)-HCl, simulating ventricle enzymic decomposition, and finally, in the third step, fresh extract from duodenal contents was used to simulate enzymic intestinal degradation of the remaining components of the food. The inoculum was normally obtained from animals which had recently eaten the prey to be tested. In such tests we obtained a dry matter disappearance (DMD) and a DE for herring (Clupea harengus) of 80.4 (SD 5.0)% (n 18) and 92.1 (SD 3.7)% (n 16) respectively, and a DMD of krill (Thysanoessa sp.) of 83.4 (SD 4.9)% (n 6). The DMD of krill was reduced to 73.8 (SD 7.3)% (n 8) while the DE was 70.6 (SD 10.4)% (n 7) when inoculum from whales which had recently eaten cod (Gadus morhua) and haddock (Melanogrammus aeglefinus) was used. These results indicate a high digestibility of the most common species of prey in these animals, and also that the whales have little difficulty in changing from one prey species to another.