Regulation and bioelectrical effects of cyclic adenosine monophosphate production in the ciliary epithelial bilayer.
To determine whether the intact isolated ciliary epithelial bilayer retains the alpha-2 and beta adrenergic receptor activation and interaction described for whole ciliary processes and whether this pure epithelial bilayer displays bioelectric parameters sensitive to alterations in cyclic adenosine Monophosphate (cAMP) production induced by adrenergic compounds. The intact ciliary epithelial bilayer of the rabbit eye isolated by perfusion was mounted in a specially constructed Ussing-type chamber. The transepithelial potential difference and short-circuit current were monitored for effects induced by agents that stimulated or blocked (some did both) caMP production. Using a radioimmunoassay, the latter were studied in the pure epithelial bilayers and in whole ciliary processes. A reproducible increase in cAMP production and an increase in the short-circuit current induced in the bilayer by isoproterenol, a nonspecific beta adrenergic agonist, were both blocked by pretreatment with either timolol, a nonspecific beta adrenergic blocking agent, or with para-aminoclonidine, an alpha-2 agonist. Maximal stimulation of cAMP with forskolin in this pure isolated epithelial preparation yields a response that is 60% of the value found in whole processes, indicating that the latter tissue contains responsive sites that are nonepithelial, probably vascular, or perhaps stromal. The degree of inhibition of the beta adrenergic receptor by alpha-2 agonists was not very different in the two preparations. On the other hand, inhibition of the epithelial vasointestinal peptide receptor by neuropeptide Y or alpha-2 agonism was considerably heightened in the pure bilayered epithelial preparation. The isolated intact ciliary epithelial bilayer, when stimulated with beta adrenergic receptor agonists, vasointestinal peptide, or forskolin, produces increased cAMP and its transepithelial potential becomes hyperpolarized. These chemical and bioelectrical effects are prevented by pretreatment with either alpha-2 adrenergic agonists or beta adrenergic blocking agents. The results obtained in the isolated intact purely epithelial ciliary bilayer confirm that the ciliary epithelium is the source of adrenergic receptor activation and interaction and support the hypothesis that aqueous humor production is regulated by interactions between epithelial alpha-2 and beta adrenergic receptors.


Preliminary evaluation of a microtransesophageal probe in neonates and young infants undergoing surgery for congenital heart disease.
The larger size of the currently available transesophageal echocardiography (TEE) probes limits their use to relatively older infants undergoing cardiac surgery. In very young neonates and infants, epicardial echocardiogram is used to assess postoperative residual defects. Recently, a miniaturized microTEE probe compatible in neonates has been introduced for clinical use. We evaluated the use of this probe in small infants undergoing cardiac surgery. Thirty-three consecutive neonates and infants undergoing cardiac surgery at our institution were included in the study. Intraoperative echocardiography with Philips s8-3t microTEE probe done using IE33 platform was utilized to study the preoperative anatomy and assess postoperative results. Thirty-three patients aged 3 days-2 years (mean 5.1 months) and weighing 2.5-11 kg (mean 4.4 kg) underwent perioperative evaluation using the microTEE probe. Good quality two-dimensional and color Doppler images were obtained in all patients. There were no complications related to the probe insertion or manipulation. The findings on microTEE led to revision of surgery in five patients. Certain echocardiographic parameters that could never be recorded with epicardial echocardiogram could be easily seen in microTEE. On preliminary evaluation, the microTEE probe provided good quality images in very small infants who were not amenable for transesophageal echocardiographic evaluation so far. The probe could be used safely in small infants without complications. It appears to be a promising imaging modality in the perioperative assessment of young infants undergoing cardiac surgery, in whom intraoperative epicardial echocardiography is currently the only tool.


Lymph node yield in treatment naïve cases of head and neck squamous cell carcinoma: en bloc lymphadenectomy versus level-by-level dissection.
Lymph node yield is an important prognostic factor in head and neck squamous cell carcinoma. Variability in neck dissection sampling techniques has not been studied as a determinant of lymph node yield. This retrospective study used lymph node yield and average nodes per level to compare level-by-level and en bloc neck dissection sampling methods, in primary head and neck squamous cell carcinoma cases operated between March 2017 and February 2020. From 123 patients, 182 neck dissections were analysed, of which 133 were selective and the rest were comprehensive: 55 had level-by-level sampling and 127 had undergone en bloc dissection. The level-by-level method yielded more nodes in all neck dissections combined (20 vs 17; p = 0.097), but the difference was significant only for the subcohort of selective neck dissection (18.5 vs 15; p = 0.011). However, the gain in average nodes per level achieved by level-by-level sampling was significant in both groups (4.2 vs 3.33 and 4.4 vs 3, respectively; both p < 0.001). Sampling of cervical lymph nodes level-by-level yields more nodes than the en bloc technique. Further studies could verify whether neck dissection sampling technique has any impact on survival rates.


Gemcitabine and irinotecan in locally advanced or metastatic biliary cancer: preliminary report.
Chemotherapy has had limited success in biliary tract cancer. Of the newer agents, gemcitabine (Gemzar) and irinotecan (CPT-11, Camptosar) both have single-agent activity in patients with advanced disease. We conducted a phase II trial to study the efficacy and toxicity of the combination of gemcitabine plus irinotecan in patients with locally advanced or metastatic biliary tract cancer. The study has enrolled 14 patients with histologically or cytologically documented cancer of the biliary tract or gallbladder with bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0 or 1, decompressed biliary tree, and no prior exposure to chemotherapy. Gemcitabine at 1,000 mg/m2 and irinotecan at 100 mg/m2 were both administered on days 1 and 8, every 21 days. In patients who had less than grade 3 hematologic and less than grade 2 nonhematologic toxicity following cycle 1, the dose of irinotecan was increased to 115 mg/m2 for subsequent cycles. A total of 65 cycles of chemotherapy have been administered, with an average of 4.5 cycles per patient (range: 1 to 11 cycles). The median treatment duration was 3 months (range: 0.75 to 8 months). An objective partial response was determined radiographically in two patients (14%) while stable disease for periods ranging from 4 to 11.5 months was noted in six patients (43%). Toxicity consisted of grade 3/4 neutropenia in seven patients (50%) with no episodes of febrile neutropenia, grade 3/4 thrombocytopenia in four (28%), grade 3 diarrhea in two (14%), and grade 3 nausea in one patient. The combination of gemcitabine plus irinotecan appears to possess modest clinical activity, and it is well tolerated in patients with advanced biliary cancer. Patient accrual is ongoing to this study.


OBJECTIVE MULTI-STATION CLINICAL EVALUATION IN PATHOLOGICAL ANATOMY. CRITICAL ANALYSIS AND PERCEPTION.
Multi-station objective clinical evaluation (MSOCE) is an equitable and genuine formative and normative assessment tool that is deemed relevant to its effectiveness, reliability and validity in clinical evaluation. However, no experience with its application in pathological anatomy has been published. To carry out a critical analysis and a perceptual study of the MSOCE in pathological anatomy in medical students. This was a cross-sectional, multicenter prospective study in which we developed and tested a MSOCE on 32 medical students of the 1st year of the second cycle of medical studies. Docimological analysis of the 12 stations and the 28 questions of the different stations was done by the file "AnItem.xls". The mean total score obtained at the MSOCE was 36.2/50 (range : 29 to 41). The majority of stations were of acceptable difficulty (92%) and of poor discrimination (92%). The majority of questions were easy (57%) with poor discrimination (75% of the total questions). One question on 28 was "ideal", 4%. The MSOCE had a large heterogeneity (average Cronbach alpha of 0.29), and discriminated well between the average students (platykurtic, left-spread, negatively asymmetric distribution curve). The perception analysis showed that 27 students (84%) were satisfied with the OMSCE and thought that it was close to the reality of the clinical training. The OMSCE tested was easy and discriminated mostly between average students. It was well perceived by the students and close to the reality of the clinical training. Ongoing analysis will further improve the quality of MSOCE.


Predictive Value of the International Classification of Diseases, 9th Revision Codes for Identifying Ocular Oncology Diagnoses.
The aim of this study was to determine the predictive value of International Classification of Diseases, 9th Revision (ICD-9) billing codes for identifying ocular oncology diagnoses. Population-based retrospective cohort study of all Olmsted County, Minnesota residents with any ocular neoplasm-related ICD-9 code from January 1, 2006 to October 1, 2015. All medical records were reviewed for confirmation of ocular neoplasm. Diagnoses with ≥5 cases confirmed via a medical record review were compared to corresponding ICD-9 codes. Main outcome measures included positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of ICD-9 codes. Among 3,932 subjects with ≥1 ocular neoplasm-related ICD-9 code, 21 diagnoses met study criteria. The most frequent intraocular, extraocular/orbital, and ocular surface diagnoses were choroidal nevus (n = 824), epidermal inclusion cyst (n = 263), and conjunctival nevus (n = 74), respectively. PPVs ranged from 1.2% to 73.8%, NPVs from 96.9% to 100%, sensitivity from 0% to 100%, and specificity from 85.7% to 100%. Among malignant neoplasms, PPV ranged from 0% to 73.8%: ocular surface squamous neoplasia (PPV: 0%), choroidal melanoma (PPV: 25.0%), eyelid squamous cell carcinoma (PPV: 46.7%), and eyelid basal cell carcinoma (PPV: 73.8%). Among benign neoplasms, PPV ranged from 1.2% (dermoid cyst) to 61.6% (choroidal nevus). There was a wide variation in a predictive value of ocular neoplasm-related ICD-9 billing codes, which suggests that ocular oncology-related claims data alone may overestimate the true number of ocular oncology diagnoses.


Feature encoding for unsupervised segmentation of color images.
In this paper, an unsupervised segmentation method using clustering is presented for color images. We propose to use a neural network based approach to automatic feature selection to achieve adaptive segmentation of color images. With a self-organizing feature map (SOFM), multiple color features can be analyzed, and the useful feature sequence (feature vector) can then be determined. The encoded feature vector is used in the final segmentation using fuzzy clustering. The proposed method has been applied in segmenting different types of color images, and the experimental results show that it outperforms the classical clustering method. Our study shows that the feature encoding approach offers great promise in automating and optimizing the segmentation of color images.


Twitter improves influenza forecasting.
Accurate disease forecasts are imperative when preparing for influenza epidemic outbreaks; nevertheless, these forecasts are often limited by the time required to collect new, accurate data. In this paper, we show that data from the microblogging community Twitter significantly improves influenza forecasting. Most prior influenza forecast models are tested against historical influenza-like illness (ILI) data from the U.S. Centers for Disease Control and Prevention (CDC). These data are released with a one-week lag and are often initially inaccurate until the CDC revises them weeks later. Since previous studies utilize the final, revised data in evaluation, their evaluations do not properly determine the effectiveness of forecasting. Our experiments using ILI data available at the time of the forecast show that models incorporating data derived from Twitter can reduce forecasting error by 17-30% over a baseline that only uses historical data. For a given level of accuracy, using Twitter data produces forecasts that are two to four weeks ahead of baseline models. Additionally, we find that models using Twitter data are, on average, better predictors of influenza prevalence than are models using data from Google Flu Trends, the leading web data source.


Improving the Production of Punicic Acid in Baker's Yeast by Engineering Genes in Acyl Channeling Processes and Adjusting Precursor Supply.
Punicic acid (PuA) is a high-value edible conjugated fatty acid with strong bioactivities and has important potential applications in nutraceutical, pharmaceutical, feeding, and oleochemical industries. Since the production of PuA is severely limited by the fact that its natural source (pomegranate seed oil) is not readily available on a large scale, there is considerable interest in understanding the biosynthesis and accumulation of this plant-based unusual fatty acid in transgenic microorganisms to support the rational design of biotechnological approaches for PuA production via fermentation. Here, we tested the effectiveness of genetic engineering and precursor supply in PuA production in the model yeast strain Saccharomyces cerevisiae. The results revealed that the combination of precursor feeding and co-expression of selected genes in acyl channeling processes created an effective "push-pull" approach to increase PuA content, which could prove valuable in future efforts to produce PuA in industrial yeast and other microorganisms via fermentation.


Miscarriages in families with an offspring that have classic congenital adrenal hyperplasia and 21-hydroxylase deficiency.
The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (CAH). Both men and women with classic CAH have lower fertility rates than the general population, and an increased rate of miscarriages has been reported in affected women. There are no data on the incidence rate of miscarriages in families with an offspring that have classic CAH. We studied families with a history of classic CAH. The families came from different parts of Germany and attended the annual meeting of the German CAH support group for parents and patients which was held in Hamburg in September 2014. The data was collected anonymously by a paper-based questionnaire which was completed by the families at home. The families also accepted the responsibility to address this question to their siblings. In all, the data of 50 families with at least one child with classic CAH, and the data of 164 parental siblings were available for evaluation. Miscarriage rates were calculated in relation to the reported pregnancies. Twenty-two miscarriages were reported from 19 families. At least one miscarriage occurred in 38% of the families, three families experienced two miscarriages and 16 families had one miscarriage each. The mean miscarriage rate was 15.8%. The heterozygous mothers had a total of 90 siblings (41 m, 49 f), while 74 siblings (33 m, 41 f) were reported from the heterozygous fathers. The miscarriage rate was 10.1% in the families of the mothers` siblings, and 11.4% in the families of the fathers` siblings. The genotype was known in all parents that have an offspring with classic CAH, but not defined in 82% of the maternal siblings, and in 86% of the paternal siblings. No child with classic CAH has been diagnosed in any of the sibling's families to date. Our data show that the miscarriage rate in German families with a child with classic CAH is not elevated.


Examination of the COVID-19 Pandemic's Impact on Mental Health From Three Perspectives: Global, Social, and Individual.
The extent of the deleterious effects of the COVID-19 pandemic on mental health is recognized ubiquitously. However, these effects are subject to many modulatory factors from a plethora of domains of examination. It is important to understand the intersection of societal and individual levels for global stressors compared with local phenomena and physical-health outcomes. Here, we consider three perspectives: international/cultural, social, and individual. Both the enduring threat of COVID-19 infection and the protective measures to contain contagion have important consequences on individual mental health. These consequences, together with possible remedial interventions, are the focus of this article. We hope this work will stimulate more research and will suggest factors that need to be considered in the coordination of responses to a global threat, allowing for better preparation in the future.


Activity and stability of centrosomes in Chinese hamster ovary cells in nucleation of microtubules in vitro.
Mitotic centrosomes were prepared from Chinese hamster ovary cells and their capacity to nucleate microtubules in vitro was demonstrated by incubation with exogenous brain microtubule protein. The number of microtubules polymerized onto centrosomes was directly counted by electron microscopy of whole-mount preparations. This simple and accurate quantitative assay has permitted characterization of the microtubule nucleating activity of centrosomes in vitro. The number of microtubules polymerized onto centrosomes varied according to the structure of the centrosome. The activity was roughly proportional to the centriole number. The number and length of microtubules nucleated by centrosomes depended both on the concentration of tubulin and the incubation time with tubulin. Under saturating conditions, an average of 200-250 microtubules were initiated by single centrosomes. Centrosomal activity is unstable (t 1/2 = 8 h) and could easily be irreversibly disrupted by a medium of high ionic strength. The activity is stabilized by the addition of glycerol. Centrosomes can be stored at -80 degrees C. The optimum pH for microtubule nucleation is 6.8. Activity is sensitive to protease digestion, but neither DNase or RNase affected the nucleating activity of centrosomes. The activity is temperature-sensitive, but addition of phenylmethylsulphonyl fluoride (PMSF) induces thermal stability. At an optimal concentration of 0.5 mg/ml, this drug increased the half-life of the activity (t 1/2 = 95 h) and made it resistant to salt extraction. Protease inhibitors other than PMSF or dansyl fluoride did not have any stabilizing effect on the activity. The difference between the centrosomal structure of polymerized microtubules in vivo and in vitro is discussed.


Detection of antibodies to the nonstructural 3C proteinase of hepatitis A virus.
Hepatitis A virus (HAV) infection can stimulate the production of antibodies to structural and nonstructural proteins of the virus. However, vaccination with an inactivated vaccine produces antibodies exclusively to the structural proteins. Current diagnostic assays, such as the Abbott HAVAB test, used to determine exposure to HAV detect antibodies only to the structural proteins and as a result are not able to distinguish between a natural infection and vaccination with an inactivated virus. Therefore, an ELISA was developed that is specific for antibodies to the nonstructural protein 3C of HAV and thus serves to document the occurrence of viral replication. Antibodies to the proteinase were not detected by this assay in serum from HAVAB-seropositive primates that were immunized with inactivated HAV. However, antibodies to the proteinase were detected in the serum of all primates experimentally infected with virulent HAV and in the serum of naturally infected humans.


Is Hepatobiliary Scintigraphy Sufficient to Diagnose Rotor Syndrome in a 3-Year-Old Boy?
Rotor syndrome (RS) is a benign, inherited, commonly misdiagnosed cause of conjugated hyperbilirubinemia whose identification prevents unnecessary invasive investigations. We present the case of a 3-y-old boy with phenotypic and laboratory findings of RS but negative genetic test results, whose diagnosis was confirmed by hepatobiliary scintigraphy.


White-light interference microscopy: a way to obtain high lateral resolution over an extended range of heights.
A problem with conventional techniques of interference microscopy, when profiling surfaces with an extended range of heights, is that only points on a single plane are in sharp focus. Other points, which are higher or lower, may be out of focus, with a consequent loss of lateral resolution. We show that white-light interference microscopy, with an achromatic phase-shifter, makes it possible to produce a three-dimensional representation of such surfaces with high lateral resolution over the entire range of heights.


Immunomodulatory Therapies for Renal Cell Carcinoma.
Renal Cell Carcinoma (RCC) is the most common tumor originating from the kidneys. In comparison to other solid tumors, RCC is poorly sensitive to conventional therapeutic modalities. As such, metastatic RCC (mRCC) continues to be associated with high rates of morbidity and mortality. Targeted agents have shown remarkable progress in RCC management with improved patients' outcomes, but rarely induce complete response and patients develop resistance to therapy eventually. However, it is well known that RCC represents one of the most immunogenic cancers and is able to evoke immune response naturally, thus prompted the emergence of several immunotherapeutic strategies in the management of RCC with variable degrees of success. Modulating the immune system with cytokines, vaccines, and T-cell modulating agents offer hope for the patients with RCC. This review critically summarizes the state of the art in RCC therapeutic regimen with immunomodulation agents. We will focus on the clinical data and ongoing clinical trials exploring the use of immunotherapy with different agents for RCC. In addition, different novel immunotherapeutic agents are being investigated for their combination therapy with other immune therapies or other modalities. Prospects (e.g., potential future immunological targets, combination regimens, appropriate sequencing) for immune therapies of RCC are also set forth in this work.


Test anxiety and self-esteem in senior high school students: a cross-sectional study.
In this study, it is aimed to determine the level of test anxiety and self-esteem in the high school students preparing for the university exam in Bitlis, Turkey, and to investigate the effect of test anxiety on self-esteem. Seven-hundred and twenty-four high school students who were preparing for the university entrance examination in Bitlis participated in the study. A questionnaire which includes socio-demographic data form, Rosenberg Self-Esteem Scale and Revised Test Anxiety Scale was prepared as an e-questionnaire for the students to fill easily and uploaded to the Bitlis State Hospital's website. Schools were called and informed for the students to fill out the e-questionnaire on the Internet. The most important findings from our study are that gender is influential on test anxiety and self-esteem score and test anxiety level are negatively correlated. It was observed that female students had more test anxiety than male students and those who had higher self-esteem had less test anxiety. Consequently, our study shows that university entrance examination creates anxiety on students and reduces self-esteem, especially in female students.


Sterility in mutant (tLx/tLy) male mice. II. A morphological study of spermatozoa.
A comparative light and electron microscopy study was done on cauda epididymal spermatozoa obtained from correspondingly-aged sterile t6/tw32, and fertile T/tw32, T/t6 and BALB/c, mice. The results show that all of the males, regardless of age, contained defective gametes and that all contained the same types of aberrant gametes. The oldest males of each genotype contained more abnormal gametes than the younger males of the same genotype. No unique spermatozoan defect and no increased frequency of a specific spermatozoan defect was noted which could be correlated with the sterility of the t6/tw32 animals.


Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome.
Mutations in transcription factors often contribute to human leukemias by providing a block to normal differentiation. To determine whether mutations in the hematopoietic transcription factor GATA1 are associated with leukemia, we assayed for alterations in the GATA1 gene in bone marrow samples from patients with various subtypes of acute leukemia. Here we summarize our findings that GATA1 is mutated in the leukemic blasts of patients with Down syndrome acute megakaryoblastic leukemia (DS-AMKL). We did not find mutations in GATA1 in leukemic cells of DS patients with other types of acute leukemia, or in other patients with AMKL who did not have DS. Furthermore, we did not detect GATA1 mutations in DNAs from over 75 other patients with acute leukemia or from 21 healthy individuals. Since the GATA1 mutations were restricted to DS-AMKL, we also investigated whether GATA1 was altered in the "preleukemia" of DS, transient myeloproliferative disorder (TMD). TMD is a common myeloid disorder that affects 10% of DS newborns and evolves to AMKL in nearly 30% patients. We detected GATA1 mutations in TMD blasts from every infant examined. Together, these results demonstrate that GATA1 is likely to play a critical role in the etiology of TMD and DS-AMKL, and that mutagenesis of GATA1 represents a very early event in DS myeloid leukemogenesis. We hypothesize that disruption of normal GATA-1 function is an essential step in the initiation of megakaryoblastic leukemia in DS.


Using electronic medical record notes to measure ICU telemedicine utilization.
Given the complexity of high-acuity health care, designing an effective clinical note template can be beneficial to both document patient care and clarify how telemedicine is used. We characterized documented interactions via a standardized note template between bedside intensive care unit (ICU) providers and teleintensivists in 2 Veterans Health Administration ICU telemedicine support centers. All ICUs linked to support centers and providing care from October 2012 through September 2014 were considered. Interactions were assessed based on initiation site, bedside initiator, contact type, and patient care change. Of 14 511 ICU admissions with teleintensivist access, teleintensivist interaction was documented in 21.6% (N = 3136). In particular, contacts were primarily initiated by bedside staff (74.4%), use increased over time, and of contacts resulting in changes in patient care, most were initiated by a bedside nurse (84.3%). Given this variation, future research necessitates inclusion of utilization in evaluation of Tele-ICU and patient outcomes.


The Himalayan Onion (Allium wallichii Kunth) Harbors Unique Spatially Organized Bacterial Communities.
Plant-associated microorganisms are known to contribute with various beneficial functions to the health and productivity of their hosts, yet the microbiome of most plants remains unexplored. This especially applies to wild relatives of cultivated plants, which might harbor beneficial microorganisms that were lost during intensive breeding. We studied bacterial communities of the Himalayan onion (Allium wallichii Kunth), a wild relative of onion native to mountains in East Asia. The bacterial community structure was assessed in different plant microhabitats (rhizosphere, endosphere, anthosphere) by sequencing of 16S rRNA gene fragment amplicons. Targeted bioinformatic analyses were implemented in order to identify unique features in each habitat and to map the overall community in the first representative of the Amaryllidaceae plant family. The highest bacterial diversity was found for bulk soil (Shannon index, H' 9.3) at the high-altitude sampling location. It was followed by the plant rhizosphere (H' 8.9) while communities colonizing flowers (H' 6.1) and the endosphere (H' 6.5 and 5.6) where less diverse. Interestingly, we observed a non-significant rhizosphere effect. Another specificity of the microbiome was its high evenness in taxonomic distribution, which was so far not observed in plant microbiomes. Pseudomonas was identified among additional 10 bacterial genera as a plant-specific signature. The first insights into the microbiome of a plant in the widespread Allium genus will facilitate upcoming comparisons with its domesticated relatives while additionally providing a detailed microbiome mapping of the plant's microhabitats to facilitate bioresource mining.


The effect of zolpidem on targeted memory reactivation during sleep.
According to the active system consolidation theory, memory consolidation during sleep relies on the reactivation of newly encoded memory representations. This reactivation is orchestrated by the interplay of sleep slow oscillations, spindles, and theta, which are in turn modulated by certain neurotransmitters like GABA to enable long-lasting plastic changes in the memory store. Here we asked whether the GABAergic system and associated changes in sleep oscillations are functionally related to memory reactivation during sleep. We administered the GABAA agonist zolpidem (10 mg) in a double-blind placebo-controlled study. To specifically focus on the effects on memory reactivation during sleep, we experimentally induced such reactivations by targeted memory reactivation (TMR) with learning-associated reminder cues presented during post-learning slow-wave sleep (SWS). Zolpidem significantly enhanced memory performance with TMR during sleep compared with placebo. Zolpidem also increased the coupling of fast spindles and theta to slow oscillations, although overall the power of slow spindles and theta was reduced compared with placebo. In an uncorrected exploratory analysis, memory performance was associated with slow spindle responses to TMR in the zolpidem condition, whereas it was associated with fast spindle responses in placebo. These findings provide tentative first evidence that GABAergic activity may be functionally implicated in memory reactivation processes during sleep, possibly via its effects on slow oscillations, spindles and theta as well as their interplay.


Molecular modeling of cardiac glycoside binding by the human sequence monoclonal antibody 1B3.
The amino acid sequences of the heavy- and light-chain variable regions of the high-affinity human sequence antidigoxin monoclonal antibody 1B3 (mAb 1B3) were determined, and a structural model for the mAb's variable region was developed by homology modeling techniques. The structural model provided the basis for computationally docking digoxin and eight related cardiac glycosides into the putative binding site of mAb 1B3. Analysis of the consensus binding mode obtained for digoxin showed that the cardenolide moiety of digoxin is deeply embedded in a predominantly hydrophobic, narrow cavity, whereas the terminal, gamma-carbohydrate group is solvent-exposed. The docking results indicated that the primary driving forces for digoxin binding by mAb 1B3 are hydrophobic interactions with the digoxin steroid ring system and hydrogen bonds with the digitoxose groups. The binding model accounts for the experimentally observed variations in mAb 1B3 binding affinity for various structural analogs of digoxin used previously to develop a 3D structure-activity relationship model of drug binding (Farr CD, Tabet MR, Ball WJ Jr, Fishwild DM, Wang X, Nair AC, Welsh WJ. Three-dimensional quantitative structure-activity relationship analysis of ligand binding to human sequence antidigoxin monoclonal antibodies using comparative molecular field analysis. J Med Chem 2002;45:3257-3270). In particular, the hydrogen bond pattern is consistent with the unique sensitivity of mAb 1B3's binding affinity to the number of sugar residues present in a cardiac glycoside. The hydrophobic environment about the steroid moiety of digoxin is compatible with the mAb's reduced affinity for ligands that possess hydrophilic hydroxyl and acetyl group modifications in this region. The model also indicated that most of the amino acid residues in contact with the ligand reside in or about the three complementarity determining regions (CDRs) of the heavy chain and the third CDR of the light chain. A comparison of the 1B3 binding model with the crystal structures of two murine antidigoxin mAbs revealed similar binding patterns used by the three mAbs, such as a high frequency of occurrence of aromatic, hydrophobic residues in the CDRs and a dominant role of the heavy chain CDR3 in antigen binding.


The expression pattern of c-mpl in megakaryocytes correlates with thrombotic risk in essential thrombocythemia.
Using immunohistochemistry, we investigated the expression of c-mpl in bone marrow megakaryocytes of 88 patients with essential thrombocythemia (ET), 6 patients with secondary thrombocytosis (ST), and 20 patients with lymphoma (controls). Considering both the pattern of expression and the staining intensity, we identified a uniform and a heterogeneous pattern of c-mpl expression. The uniform pattern was found in all the controls, all the patients with ST, and 28 of the patients with ET, with a strong staining intensity observed in most megakaryocytes (> 80%). In contrast, c-mpl expression was heterogeneous in 60 patients with ET, 18 of whom (30%) presented with thrombosis at diagnosis, a significant difference from patients with a uniform c-mpl pattern (2 of 28; 7%; P =.026). In particular, the overrepresentation of thrombotic complications in patients with a heterogeneous c-mpl expression pattern was found mainly among patients with a significant percentage (10% to 40%) of weakly stained or c-mpl-negative megakaryocytes (heterogeneous-weak pattern; 13 of 30; 43%; P =.002). Accordingly, this pattern was associated with a 6.1-fold increased risk of thrombosis compared with that of patients with a uniform c-mpl pattern. In conclusion, the presence of a heterogeneous pattern of c-mpl distribution in bone marrow megakaryocytes could be a useful diagnostic criterion in the differential diagnosis of thrombocytosis. Furthermore, detection of a significant percentage of weakly stained or c-mpl-negative megakaryocytes can identify patients with a higher risk of thrombosis.


Novel neuronal targets for the acetylcholinesterase inhibitor donepezil.
The effects of the acetylcholinesterase inhibitor donepezil on cell viability and proliferation events have been analysed in SH-SY5Y human neuroblastoma cells. Short- (48 h) or long-term (7 days) exposure of SH-SY5Y cells to donepezil (100 nM-10 microM) induced a concentration-dependent inhibition of cell proliferation that was not modified by muscarinic and nicotinic receptor antagonists, or mimicked by galantamine, and was not related to induction of apoptosis. By analysing the distribution profile of cell populations within the cell cycle following treatment with 10 microM donepezil, a reduction of cells in the S-G2/M phases of the cycle and a parallel increase of the G0/G1 population were observed. In addition, the expression of two cyclins of the G1/S and G2/M transitions, cyclin E and cyclin B, was significantly reduced in donepezil-treated cells. In contrast, the expression of the cell cycle inhibitor p21 rapidly (6 h) increased following exposure to the drug. Finally, donepezil increased the expression of the neuronal marker MAP-2 in selected subpopulations of SH-SY5Y cells, suggesting that the effect on cell proliferation by donepezil may correlate to a trend to neuronal differentiation.


Intergenerational Interactions and Relationship Quality: A Daily Study among Mothers and Their Adult Children.
The parent-child relationship is one of the most long-lasting relationships in human life. Such relationship is particularly adaptive during public health emergencies that threaten human life. However, few studies have examined the effects of daily exchanges in support between aging parents and adult children on the relationship quality during public health emergencies. Using data collected during the COVID-19 pandemic, we examined the relationship between daily support and relationship quality among middle-aged and older mothers and adult children. Seventy-seven dyads of middle-aged and older mothers (age range: 44-80 years, Mage = 53.78, SDage = 9.57) and adult children (age range: 18-54 years, Mage = 26.61, SDage = 9.46) participated in the study. They reported their daily exchanges with the other (i.e. support they had received from and given to each other) and daily relationship quality (i.e. relationship satisfaction and trust) each day for 14 consecutive days. The perception of being under-benefited on Day N was associated with daily relationship satisfaction on the concurrent day in children but not mothers. It was associated with daily trust towards the relationship partner in both mothers and children on Day N. Both providing and receiving more support on Day N was associated with better relationship satisfaction for both mothers and children on Day N. Only receiving (not providing) more support on Day N was associated with greater trust toward the partner on Day N for both mothers and children. The time-lagged associations were not significant. The findings highlight the importance of daily reciprocity and daily support exchanges on relationship quality during a public health emergency.


Categorical speech processing in Broca's area: an fMRI study using multivariate pattern-based analysis.
Although much effort has been directed toward understanding the neural basis of speech processing, the neural processes involved in the categorical perception of speech have been relatively less studied, and many questions remain open. In this functional magnetic resonance imaging (fMRI) study, we probed the cortical regions mediating categorical speech perception using an advanced brain-mapping technique, whole-brain multivariate pattern-based analysis (MVPA). Normal healthy human subjects (native English speakers) were scanned while they listened to 10 consonant-vowel syllables along the /ba/-/da/ continuum. Outside of the scanner, individuals' own category boundaries were measured to divide the fMRI data into /ba/ and /da/ conditions per subject. The whole-brain MVPA revealed that Broca's area and the left pre-supplementary motor area evoked distinct neural activity patterns between the two perceptual categories (/ba/ vs /da/). Broca's area was also found when the same analysis was applied to another dataset (Raizada and Poldrack, 2007), which previously yielded the supramarginal gyrus using a univariate adaptation-fMRI paradigm. The consistent MVPA findings from two independent datasets strongly indicate that Broca's area participates in categorical speech perception, with a possible role of translating speech signals into articulatory codes. The difference in results between univariate and multivariate pattern-based analyses of the same data suggest that processes in different cortical areas along the dorsal speech perception stream are distributed on different spatial scales.


Group mentorship for undergraduate medical students-a systematic review.
Mentoring has become a prevalent educational strategy in medical education, with various aims. Published reviews of mentoring report very little on group-based mentorship programs. The aim of this systematic review was to identify group-based mentorship programs for undergraduate medical students and describe their aims, structures, contents and program evaluations. Based on the findings of this review, the authors provide recommendations for the organization and assessment of such programs. A systematic review was conducted, according to PRISMA guidelines, and using the databases Ovid MEDLINE, EMBASE, PsycINFO and ERIC up to July 2019. Eight hundred abstracts were retrieved and 20 studies included. Quality assessment of the quantitative studies was done using the Medical Education Research Study Quality Instrument (MERSQI). The 20 included studies describe 17 different group mentorship programs for undergraduate medical students in seven countries. The programs were differently structured and used a variety of methods to achieve aims related to professional development and evaluation approaches. Most of the studies used a single-group cross-sectional design conducted at a single institution. Despite the modest quality, the evaluation data are remarkably supportive of mentoring medical students in groups. Group mentoring holds great potential for undergraduate medical education. However, the scientific literature on this genre is sparse. The findings indicate that group mentorship programs benefit from being longitudinal and mandatory. Ideally, they should provide opportunities throughout undergraduate medical education for regular meetings where discussions and personal reflection occur in a supportive environment.


A Novel High-Throughput 3D Screening System for EMT Inhibitors: A Pilot Screening Discovered the EMT Inhibitory Activity of CDK2 Inhibitor SU9516.
Epithelial-mesenchymal transition (EMT) is a crucial pathological event in cancer, particularly in tumor cell budding and metastasis. Therefore, control of EMT can represent a novel therapeutic strategy in cancer. Here, we introduce an innovative three-dimensional (3D) high-throughput screening (HTS) system that leads to an identification of EMT inhibitors. For the establishment of the novel 3D-HTS system, we chose NanoCulture Plates (NCP) that provided a gel-free micro-patterned scaffold for cells and were independent of other spheroid formation systems using soft-agar. In the NCP-based 3D cell culture system, A549 lung cancer cells migrated, gathered, and then formed multiple spheroids within 7 days. Live cell imaging experiments showed that an established EMT-inducer TGF-β promoted peripheral cells around the core of spheroids to acquire mesenchymal spindle shapes, loss of intercellular adhesion, and migration from the spheroids. Along with such morphological change, EMT-related gene expression signatures were altered, particularly alteration of mRNA levels of ECAD/CDH1, NCAD/CDH2, VIM and ZEB1/TCF8. These EMT-related phenotypic changes were blocked by SB431542, a TGF-βreceptor I (TGFβR1) inhibitor. Inside of the spheroids were highly hypoxic; in contrast, spheroid-derived peripheral migrating cells were normoxic, revealed by visualization and quantification using Hypoxia Probe. Thus, TGF-β-triggered EMT caused spheroid hypoplasia and loss of hypoxia. Spheroid EMT inhibitory (SEMTIN) activity of SB431542 was calculated from fluorescence intensities of the Hypoxia Probe, and then was utilized in a drug screening of EMT-inhibitory small molecule compounds. In a pilot screening, 9 of 1,330 compounds were above the thresholds of the SEMTIN activity and cell viability. Finally, two compounds SB-525334 and SU9516 showed SEMTIN activities in a dose dependent manner. SB-525334 was a known TGFβR1 inhibitor. SU9516 was a cyclin-dependent kinase 2 (CDK2) inhibitor, which we showed also had an EMT-inhibitory activity. The half maximal inhibitory concentration (IC50) of SB-525334 and SU9516 were 0.31 μM and 1.21 μM, respectively, while IC50 of SB431542 was 2.38 μM. Taken together, it was shown that this 3D NCP-based HTS system was useful for screening of EMT-regulatory drugs.


Expression of GMFB in High-Grade Cervical Intraepithelial Neoplasia and Its Role in Cervical Cancer.
Cervical intraepithelial neoplasia (CIN) is a collective term for specific precancerous lesions associated with cervical cancer (CC). Although it has been affirmed with slow development of several levels of cellular changes, the existing poor prognosis calls for an urgent need to diagnose CIN at early stage and be aware of markers related to its pathogenesis and prognosis. We explored the expression level of a newly marker GMFB and its regulatory effect on CIN and CC. Patient samples and cell models were included. Bioinformatic studies were taken to predict its binding to miR-143-3p, miR-26b-5p, miR-191-5p, and miR-223-3p. Luciferase reporter and RNA pull-down assays were used to validate the prediction. Edu assay and flow cytometry were used to measure the regulation of GMFB on proliferation and apoptosis of CC cells. qRT-PCR was used for mRNA expression level detection. The results showed that GMFB was targeted by miR-143-3p, miR-26b-5p, miR-191-5p, and miR-223-3p. It had elevated expression in both CIN and CC samples. GMFB had highly prognostic value for CIN, and lymph node metastasis of CC was much associated with high GMFB expression level. Besides, silencing of GMFB inhibited CC cell proliferation and elevated cell apoptosis. In conclusion, we determined that GMFB has regulatory effect on high grade CIN and CC, which could lighten a novel way in exploring their pathogenesis and improving accuracy of prognosis.


[Scintigraphic evaluation of the ischemically damaged myocardium in patients with reduced left ventricular function. From clinical aspects to the cell].
Identification of viable myocardium in patients with impaired left ventricular function, who are possible candidates for revascularization, represents an important clinical question. Modern methods of revascularization provide a therapeutic alternative to conventional pharmacological therapy even in patients with advanced ischemic heart disease. Modern diagnostic techniques make it possible to assess not only the extent of ischemia under exercise conditions, but also the presence of viable tissue in patients with severe coronary artery disease and impaired ventricular function. Currently, the most accurate methods for scintigraphic quantification of viable myocardial tissue are metabolic investigations with positron emission tomography (PET). Because of the limited availability of PET other methods like thallium-201-scintigraphy play an important clinical role. Modifications of thallium-201-scintigraphy, for example the introduction of reinjection protocols have improved the recognition of viable tissue and decreased the diagnostic difference to PET. We recommend as standard diagnostic procedure for assessment of tissue viability thallium-201-scintigraphy with reinjection. In patients with severely depressed left ventricular function and equivocal thallium-201-scintigraphy findings, PET should be considered as further diagnostic test. Low dose dobutamine-echocardiography is emerging as alternative test for evaluation of contractile reserve in dysfunctioning left ventricular segments. Its clinical role, however, remains to be determined. Besides the clinical application of these methods, newly developed radiotracers, together with PET, may provide insights into the mechanism of metabolic adaptations in patients with repeated episodes of ischemia. Furthermore, correlation of clinical data with in vitro histological and biological tissue analysis in the same patients may provide a better understanding of metabolic alterations observed in chronic ischemic heart disease.


Hemorrhagic peripheral pigment epithelial disease.
Hemorrhage under the retinal pigment epithelium and neurosensory retina occurred in the temporal periphery of ten patients with aging macular degeneration and one patient with histoplasmosis syndrome. The macula was not the source of bleeding. Peripheral subretinal neovascularization, commonly seen histopathologically, may be the cause. The visual recovery was poor, and most patients failed to regain lost vision once peripheral hemorrhage occurred. The differential diagnosis includes retinal detachment, uveal effusion, hemorrhagic retinoschisis, choroidal melanoma, and metastatic tumor.


Patterns of p53 G-->T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke.
It is unquestionable that the major cause of lung cancer is cigarette smoking. p53 mutations are common in lung cancers from smokers but less common in non-smokers. A large fraction of the p53 mutations in lung cancers are G-->T transversions, a type of mutation that is infrequent in other tumors aside from hepatocellular carcinoma. Previous studies have indicated that there is a good correlation between G-->T transversion hotspots in lung cancers and sites of preferential formation of polycyclic aromatic hydrocarbon (PAH) adducts along the p53 gene. The origin of p53 mutations in lung cancer has been questioned by recent reports suggesting that there are no significant differences in p53 mutation spectra between smokers and non-smokers and between lung cancers and non-lung cancers [S.N. Rodin and A.S. Rodin (2000) Human lung cancer and p53: The interplay between mutagenesis and selection. P:roc. Natl Acad. Sci. USA, 97, 12244-12249]. We have re-assessed these issues by using the latest update of the p53 mutation database of the International Agency for Research on Cancer (14 051 entries) as well as recent data from the primary literature on non-smokers. We come to the conclusion that the p53 mutation spectra are different between smokers and non-smokers and that this difference is highly statistically significant (G-->T transversions are 30 versus 10%; P < 0.0001, chi2 test). A similar difference is seen between lung cancers and non-lung cancers. At a number of mutational hotspots common to all cancers, a large fraction of the mutations are G-->T transversions in lung cancers but are almost exclusively G-->A transitions in non-lung cancers. Our data reinforce the notion that p53 mutations in lung cancers can be attributed to direct DNA damage from cigarette smoke carcinogens rather than to selection of pre-existing endogenous mutations.


The Impact of Antidepressant Therapy on Glycemic Control in Canadian Primary Care Patients With Diabetes Mellitus.
Context: Depression is common in people with diabetes and is associated with poor glycemic control. Evidence suggests that certain antidepressants (AD) increase the risk of poor control. Few population-based studies have examined the impact of individual ADs on glycemic control. This study's objective is to measure the impact of Citalopram, Amitriptyline, Venlafaxine, Trazodone and Escitalopram on glycated hemoglobin (HbA1c) in Canadian primary care patients with diabetes. Methods: A retrospective study of electronic medical records (EMR) from 115 primary care practices across Canada was undertaken. Data were obtained from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN). The sample population comprised 1,084 diabetic patients with 1,127 prescriptions of one of the five selected ADs and with baseline and post-exposure HbA1c measurements. Generalized linear mixed models were computed to estimate the effect of the ADs on HbA1c. Results: Mean HbA1c ratios for Amitriptyline, Venlafaxine, Trazodone and Escitalopram were all numerically lower than Citalopram. The confidence intervals included the minimum detectable effect, however the differences were not statistically significant. The lowest clinically relevant HbA1c ratios, relative to Citalopram, were found in patients prescribed Trazodone and Escitalopram. Accounting for the prescription of Trazodone for indications other than depression, this research suggests that Escitalopram may be safer than Citalopram for people with diabetes and depression, in terms of its effect on blood glucose. Conclusion: This study can inform future research examining the relationship between ADs and blood glucose and provides insight into the limitations pertaining to the use of health data in health research. Future research should seek to control for, across multiple time points: depression symptoms, depression severity, depression duration, weight, diabetes medication, tobacco and alcohol consumption and other medications with a known impact on blood glucose.


Bifidobacterium infantis associates with T cell immunity in human infants and is sufficient to enhance antigen-specific T cells in mice.
Bacille Calmette-Guerin (BCG) vaccine can elicit good TH1 responses in neonates. We hypothesized that the pioneer gut microbiota affects vaccine T cell responses. Infants who are HIV exposed but uninfected (iHEU) display an altered immunity to vaccination. BCG-specific immune responses were analyzed at 7 weeks of age in iHEU, and responses were categorized as high or low. Bifidobacterium longum subsp. infantis was enriched in the stools of high responders, while Bacteroides thetaiotaomicron was enriched in low responders at time of BCG vaccination. Neonatal germ-free or SPF mice orally gavaged with live B. infantis exhibited significantly higher BCG-specific T cells compared with pups gavaged with B. thetaiotaomicron. B. infantis and B. thetaiotaomicron differentially affected stool metabolome and colonic transcriptome. Human colonic epithelial cells stimulated with B. infantis induced a unique gene expression profile versus B. thetaiotaomicron. We thus identified a causal role of B. infantis in early-life antigen-specific immunity.


Impact of preoperative maintenance or interruption of aspirin on thrombotic and bleeding events after elective non-cardiac surgery: the multicentre, randomized, blinded, placebo-controlled, STRATAGEM trial.
Patients receiving anti-platelet agents for secondary cardiovascular prevention frequently require non-cardiac surgery. A substantial proportion of these patients have their anti-platelet drug discontinued before operation; however, there is uncertainty about the impact of this practice. The aim of this study was to compare the effect of maintenance or interruption of aspirin before surgery, in terms of major thrombotic and bleeding events. Patients treated with anti-platelet agents for secondary prevention and undergoing intermediate- or high-risk non-cardiac surgery were included in this multicentre, randomized, placebo-controlled, trial. We substituted non-aspirin anti-platelets with aspirin (75 mg daily) or placebo starting 10 days before surgery. The primary outcome was a composite score evaluating both major thrombotic and bleeding adverse events occurring within the first 30 postoperative days weighted by their severity (weights were established a priori using a Delphi consensus process). Analyses followed the intention-to-treat principle. We randomized 291 patients (n=145, aspirin group, and n=146, placebo group). The most frequent surgical procedures were orthopaedic surgery (52.2%), abdominal surgery (20.6%), and urologic surgery (15.5%). No significant difference was observed neither in the primary outcome score [mean values (SD)=0.67 (2.05) in the aspirin group vs 0.65 (2.04) in the placebo group, P=0.94] nor at day 30 in the number of major complications between groups. In these at-risk patients undergoing elective non-cardiac surgery, we did not find any difference in terms of occurrence of major thrombotic or bleeding events between preoperative maintenance or interruption of aspirin.


LUCAT1 inhibits ferroptosis in bladder cancer by regulating the mRNA stability of STAT3.
In this study, we aimed to elucidate the role of LUCAT1, a recently identified lncRNA, in ferroptosis within the context of bladder cancer (BC). Through a comprehensive array of experimental techniques, including transmission electron microscopy (TEM), RNA pull-down assays, and fluorescence in situ hybridization (FISH), we investigated the molecular interactions and functional consequences associated with LUCAT1 in BC cells. Our findings indicate that LUCAT1 acts as a pivotal regulator in BC, fostering cell proliferation, migration, and invasion, while concurrently impeding ferroptosis. Mechanistically, we unveiled a direct binding between LUCAT1 and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which governs the mRNA stability of signal transducer and activator of transcription 3 (STAT3). Intriguingly, ectopic expression of STAT3 counteracted the suppressive effect of LUCAT1 on ferroptosis induction in BC cells. Notably, in an in vivo setting, LUCAT1 emerged as a crucial modulator of ferroptosis inhibition in BC by regulating STAT3 mRNA stability. Collectively, our study identifies LUCAT1 as a novel oncogenic player, repressing ferroptosis in BC. These findings shed light on the intricate interplay between lncRNAs and ferroptosis in cancer, implicating LUCAT1 as a promising therapeutic target for patients afflicted with BC. Further investigations into the underlying mechanisms governing LUCAT1-mediated ferroptosis resistance are warranted, with the potential to uncover novel strategies for combating BC progression and improving patient outcomes.


High throughput screening for inhibitors of the HECT ubiquitin E3 ligase ITCH identifies antidepressant drugs as regulators of autophagy.
Inhibition of distinct ubiquitin E3 ligases might represent a powerful therapeutic tool. ITCH is a HECT domain-containing E3 ligase that promotes the ubiquitylation and degradation of several proteins, including p73, p63, c-Jun, JunB, Notch and c-FLIP, thus affecting cell fate. Accordingly, ITCH depletion potentiates the effect of chemotherapeutic drugs, revealing ITCH as a potential pharmacological target in cancer therapy. Using high throughput screening of ITCH auto-ubiquitylation, we identified several putative ITCH inhibitors, one of which is clomipramine--a clinically useful antidepressant drug. Previously, we have shown that clomipramine inhibits autophagy by blocking autophagolysosomal fluxes and thus could potentiate chemotherapy in vitro. Here, we found that clomipramine specifically blocks ITCH auto-ubiquitylation, as well as p73 ubiquitylation. By screening structural homologs of clomipramine, we identified several ITCH inhibitors and putative molecular moieties that are essential for ITCH inhibition. Treating a panel of breast, prostate and bladder cancer cell lines with clomipramine, or its homologs, we found that they reduce cancer cell growth, and synergize with gemcitabine or mitomycin in killing cancer cells by blocking autophagy. We also discuss a potential mechanism of inhibition. Together, our study (i) demonstrates the feasibility of using high throughput screening to identify E3 ligase inhibitors and (ii) provides insight into how clomipramine and its structural homologs might interfere with ITCH and other HECT E3 ligase catalytic activity in (iii) potentiating chemotherapy by regulating autophagic fluxes. These results may have direct clinical applications.


Does racial variation in risk factors explain black-white differences in the incidence of hypertensive end-stage renal disease?
Prospectively collected data on the incidence of treated hypertensive end-stage renal disease (HT-ESRD) were analyzed to investigate whether the higher rate of HT-ESRD in blacks compared with whites is due to differences in putative ESRD risk factors. The overall age-adjusted relative risks of HT-ESRD for black compared with white residents in the Maryland Regional ESRD Registry (Network 31) Catchment Area were 7.4 (95% confidence interval, 5.9 to 9.4) and 9.9 (95% confidence interval, 7.4 to 13.1) for men and women, respectively. In a population level analysis, race-specific HT-ESRD incidence rates in the black and white populations of 13 regions in Network 31 were related to the prevalence of putative ESRD risk factors in those populations. The latter were estimated from the 1981-1982 Maryland Statewide Household Hypertension Survey. Black populations had a 5.6-fold (95% confidence interval, 3.9 to 8.1) higher unadjusted incidence of HT-ESRD than white populations. The HT-ESRD incidence in a population was also directly related to that population's prevalence of hypertension, severe hypertension, and diabetes mellitus and inversely related to measures of socioeconomic status and mean age at diagnosis of hypertension. When adjusted simultaneously for age, prevalence of hypertension, severe hypertension, diabetes, and level of education, the risk of HT-ESRD was still 4.5 (95% confidence interval, 3.2 to 6.2) times higher for black compared with white populations. Our findings failed to support the hypothesis that race-related differences in the prevalence, severity, or age at onset of hypertension, in the prevalence of diabetes or in socioeconomic status, explain the well-recognized black-white differences in the HT-ESRD incidence.


Thrombin induces thrombomodulin mRNA expression via the proteolytically activated thrombin receptor in cultured bovine smooth muscle cells.
Thrombin, an important mitogen governing smooth muscle cell proliferation, binds to cultured bovine aortic smooth muscle cells (BASMCs) via both the proteolytically activated thrombin receptor (PATR) and thrombomodulin (TM). Although TM mRNA expression and functional activity is regulated by thrombin in human endothelial cells and mouse hemangioma cells, it remains unclear in those models whether the increased TM mRNA expression observed upon thrombin stimulation is mediated through the activation of PATR or via TM occupancy. We observed in cultured BASMCs that TM mRNA is increased threefold to sixfold by either thrombin, basic fibroblast growth factor (bFGF), or platelet-derived growth factor (PDGF). The increase in TM mRNA with thrombin is time dependent (maximal at 3 hours), a consequence of increased mRNA stability, and accompanied by increases in cell surface TM functional activity. Thrombin-induced TM mRNA was reproduced by the hexameric thrombin receptor-activating peptide (TRAP6) and augmented by a TM-specific antibody. Together, these data suggest that up-regulation of TM mRNA by thrombin is mediated via the PATR. We speculate that increases in BASMC TM mRNA and activity after thrombin may contribute to the impaired thrombus formation observed after atherosclerotic vascular injury.


Leptin: an essential regulator of lipid metabolism.
This paper reviews the general mechanisms by which leptin acts as a regulator of lipid reserves through changes in food intake, energy expenditure and fuel selection, with an emphasis on its direct effects on cellular lipid metabolism. Briefly, when leptin levels increase, food consumption decreases via modulation of hypothalamic neuropeptides. As well, normal decreases in energy expenditures (e.g. with diurnal cycles or reduced caloric intake) do not occur. This is probably caused by an increase in mitochondrial proton leak mediated by leptin via increases in sympathetic nervous system stimulation and thyroid hormone release. The decrease in caloric input coupled with relatively higher energy expenditure, therefore, leads to negative energy balance. Leptin also changes the fuel source from which ATP is generated. Fuel preference switches from carbohydrate (glucose) to lipid (fatty acids). This effect arises through stimulation of triacylglycerol catabolism by leptin. In vitro studies show that leptin is a potent stimulator of lipolysis and fatty acid oxidation in adipocytes and other cell types. Consequently, leptin is also a regulator of cellular triacylglycerol content. Hormonal regulation of leptin, as well as its role in fasting and seasonal weight gain and energy expenditure are also briefly discussed.


[Evaluation of the quality of life of patients with a Chiari type I malformation. A pilot study in a cohort of 67 patients].
The Chiari type I malformation (CM-I) is a low prevalence disorder whose manifestations vary highly, depending on the associated malformative complex. The people with a CM-I can suffer anxiety, depression symptoms and an un-defined loss of quality of life. The main purpose of this study is to establish the impact of CM-I on quality of life, as well as the presence of anxiety and depression in these patients. Prospective study of a cohort of 67 patients suffering from CM-I who undergo an evaluation by means of the SIP scale (Sickness Impact Profile), STAI (State-Trait Anxiety Inventory) and BDI (Beck's Depression Inventory) of their quality of life and of the presence of anxiety and depressive symptoms respectively. For every patient the degree of cerebellar tonsillar ectopia and the presence of syringomyelia and/or hydrocephalus were registered. The impact of the CM-I on the quality of life was none for 6 patients (9%), mild for 36 (53.7%), moderate for 17 (25.4%) and severe for 8 (11.9%). The most affected area of activity was work. A total of 86.6% of the patients presented a moderate or high anxiety level. In 25.4% of the patients moderate or severe depressive symptoms were also acknowledged. The great majority of patients with a CM-I consider that their disorder implies a loss of their quality of life which, in many cases, is associated with high anxiety and depressive symptoms.


Breast cancer: agenda setting through activism.
Breast cancer has long been one of the leading causes of death among women in the United States. The disease did not gain serious attention in the public policy arena, however, until the 1990s. Using Kingdon's agenda-setting model as a framework, this article describes how breast cancer moved to a place of prominence on the national health care agenda. The role of breast cancer activists in this effort is examined. Suggestions are then made concerning why and how advanced practice nurses might effectively influence the health policy agenda through political activism.


[Immunological indices in acquired heart defects after heart valve replacement with bioprostheses].
The indices of cellular and humoral immunity were studied in 46 patients with heart diseases of rheumatic origin prior to and alter operation for replacement of the heart valves with synthetic prostheses (in 19) and pig aortic valves treated with glutaraldehyde and methaperiodate solutions ater Karpantje (in 27). The indirect fluorescence method and the leukocyte migration inhibition test to the myocardial antigens showed that the operation for valve prosthetics causes an increase in the content of antibodies and activation of specific leukocyte sensitization to the antigens of the myocardium and heart valves. These changes do not depend on the type of the valve prosthesis and are normalized by the 6th month. The activation of immunological processes encountered in some patients in late periods after the operation (1-8 years) corresponded to an aggravation of their clinical condition which in most cases was not associated with impaired functioning of the biological prosthesis. The implantation of xenogenous valve prostheses treated by Karpantje's method did not cause the development of immunological processes which could have induced destruction of the prostheses.


Twice-Weekly Structured Interdisciplinary Bedside Rounds and Falls among Older Adult Inpatients.
Ineffective interdisciplinary communication has negative impacts on patient outcomes. The use of regular structured interdisciplinary bedside rounds (SIBR), where each patient interaction lasts 3-5 minutes, is a model of care that improves interdisciplinary communication. We evaluated the impact of SIBR on in-hospital falls. Prospective before-after study of older people hospitalized with acute illness. Two side-by-side aged care wards in a university hospital in Sydney, Australia. A total of 3,673 consecutive inpatients of mean age 83.8 ± 7.7 years, with 1,703 before SIBR compared with 1,970 after SIBR. No patients were excluded from potential participation. Twice-weekly SIBR. Falls data were manually extracted from a mandatory institutional incident reporting database. Medical diagnoses were based on the Australian Refined Diagnosis Related Groups classification system. Injuries due to falls were corroborated using the institutional electronic medical record (Cerner PowerChart). Generalized estimating equations were used to evaluate the incidence rate ratio (IRR) of falls and fall-related injuries. A negative binomial distribution and a logarithmic link function were used to linearize regression equations. After SIBR, there were 7.4 falls per 1,000 occupied bed days (OBD), compared with 10.6 falls per 1,000 OBD before SIBR (P < .001). The implementation of SIBR reduced falls (IRR = 0.67, 95% CI = 0.52-0.85), after adjusting for age, gender, cognitive impairment, behavioral and psychological symptoms of dementia, deconditioning and frailty, but not fall-related injuries (IRR = 0.79, 95% CI = 0.52-1.20). This study is the first to investigate the effect of SIBR on in-hospital falls. It provides evidence that a sustainable, twice-weekly intervention is associated with a reduction in falls. It has the potential to be used in other settings where falls are frequent.


Dioxygen Binding to Protonated Heme in the Gas Phase, an Intermediate Between Ferric and Ferrous Heme.
With a view to characterizing the influence of the electronic structure of the Fe atom on the nature of its bond with dioxygen (O2 ) in heme compounds, a study of the UV/Vis action spectra and binding energies of heme-O2 molecules has been undertaken in the gas phase. The binding reaction of protonated ferrous heme [FeII -hemeH]+ with O2 has been studied in the gas phase by determining the equilibrium of complexed [FeII -hemeH(O2 )]+ with uncomplexed protonated heme in an ion trap at controlled temperatures. The binding energy of O2 to the Fe atom of protonated ferrous heme was obtained from a van't Hoff plot. Surprisingly, this energy (1540±170 cm-1 , 18.4±2 kJ mol-1 ) is intermediate between those of ferric heme and ferrous heme. This result is interpreted in terms of a delocalization of the positive charge over the porphyrin cycle, such that the Fe atom bears a fractional positive charge. The resulting electron distribution on the Fe atom differs notably from that of a purely low-spin ferrous heme [FeII -heme(O2 )] complex, as deduced from its absorption spectrum. It also differs from that of ferric heme [FeIII -heme(O2 )]+ , as evidenced by the absorption spectra. Protonated heme creates a specific bond that cannot accommodate strong σ donation.


Cannabidiol protects livers against nonalcoholic steatohepatitis induced by high-fat high cholesterol diet via regulating NF-κB and NLRP3 inflammasome pathway.
Cannabidiol (CBD), an abundant nonpsychoactive constituent of marijuana, has been reported previously to protect against hepatic steatosis. In this study, we studied further the functions and mechanisms of CBD on liver inflammation induced by HFC diet. Mice feeding an HFC diet for 8 weeks were applied to test the protective effect of CBD on livers. RAW264.7 cells were incubated with LPS + ATP ± CBD to study the mechanisms of the effect of CBD against inflammasome activation. We found that CBD alleviated liver inflammation induced by HFC diet. CBD significantly inhibited the nuclear factor-κappa B (NF-κB) p65 nuclear translocation and the activation of nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome both in vivo and in vitro studies, which lead to the reduction of the expression of inflammation-related factors in our studies. In addition, Inhibitor of activation of NF-κB partly suppressed the NLRP3 inflammasome activation, while adding CBD further inhibited NF-κB activation and correspondingly suppressed the NLRP3 inflammasome activation in macrophages. In conclusion, the suppression of the activation of NLRP3 inflammasome through deactivation of NF-κB in macrophages by CBD might be one mechanism of its anti-inflammatory function in the liver.


Combined effects of nitrate and medium-chain fatty acids on methane production, rumen fermentation, and rumen bacterial populations in vitro.
This study investigated the combined effects of nitrate (NT) and medium-chain fatty acids (MCFA), including C8, C10, C12, and C14, on methane (CH4) production, rumen fermentation characteristics, and rumen bacteria using a 24 h batch incubation technique. Four types of treatments were used: control (no nitrate, no MCFA), NT (nitrate at 3.65 mM), NT + MCFA (nitrate at 3.65 mM + one of the four MCFA at 500 mg/L), and NT + MCFA/MCFA (nitrate at 3.65 mM + a binary combination of MCFA at 250 and 250 mg/L). All treatments decreased (P < 0.001) methanogenesis (mL/g dry matter incubated) compared with the control, but their efficiency was dependent on the MCFA type. The most efficient CH4 inhibitor was the NT + C10 treatment (- 40%). The combinations containing C10 and C12 had the greatest effect on bacterial alpha and beta diversity and relative microbial abundance (P < 0.001). Next-generation sequencing showed that the family Succinivibrionaceae was favored in treatments with the greatest CH4 inhibition at the expense of Prevotella and Ruminococcaceae. Furthermore, the relative abundance of Archaea decreased (P < 0.05) in the NT + C10 and NT + C10/C12 treatments. These results confirm that the combination of NT with MCFA (C10 and C12 in particular) may effectively reduce CH4 production.


Evaluation of carnitine, acetylcarnitine and isovalerylcarnitine on immune function and apoptosis.
The pool of different carnitine derivatives is formed by carnitine, acetylcarnitine, propionylcarnitine and isovalerylcarnitine. Isovalerylcarnitine is a compound performing activities that differ from those of the other carnitine esters. Its activity on proteolytic enzymes and on the calpain system has been demonstrated in the past. Both the calpain and the caspase systems belong to the protease family and lead to cytochrome activation and apoptosis. The two systems can interact to promote apoptosis. In view of this proapoptotic activity of isovalerylcarnitine, studies were carried out to ascertain whether this carnitine derivative influences cell-reaction processes associated with apoptosis. U937 leukemic cells were selected for these studies because they are a well-established model for the assessment of cellular immune responses. In addition to nuclear morphologic alterations produced by apoptosis that can be detected by specific histochemical and microscopic methods, we also took other cell functions into consideration, such as phagocytosis, cell killing and cell growth, which are indices of immune function related to apoptosis. Unlike reference carnitine forms, isovalerylcarnitine produced an early and marked increase in phagocytosis and also an increase in cell killing. Cell proliferation was reduced. The hypothesis is set forth that isovalerylcarnitine may be a caspase-activating, proapoptotic factor that resembles various anticancer agents, which induce early apoptosis that coincides with early activation of caspase. This hypothesis is supported by the ability of isovalerylcarnitine to induce early phagocytosis and cell killing.


Patient movements and the accuracy of the age--sex register.
This longitudinal study assessed the effects of patient movements on the accuracy of the age-sex register. For one year all patient movements into and out of five teaching practices were monitored and the ways in which inflation and deflation of the register can occur were identified and measured. Inflation has a greater influence than deflation on the accuracy of the register because:1. Practices can readily identify all new patients as they register and can include them in the age-sex register, but only a minority of patients (23.5 per cent) can be identified when they move away.2. The time interval between leaving a practice and registering with a new one is much shorter than that between leaving a practice and the practice becoming aware of the fact.Recommendations are made about how to make the register as accurate as possible.


Adrenomedullin dilates rat pulmonary artery rings during hypoxia: role of nitric oxide and vasodilator prostaglandins.
Hypoxia decreases vasorelaxation and leads to pulmonary arterial hypertension. A newly identified 52 amino-acid peptide adrenomedullin (ADM) exerts vasodilator effect in intact animals under normoxic condition. We studied the effect of human ADM on rat pulmonary arterial and aortic rings under normoxic and hypoxic conditions. During normoxia, ADM caused a concentration-dependent relaxation of precontracted aortic and pulmonary arterial rings; the relaxation was much more pronounced in pulmonary arterial rings and was abolished by the nitric oxide (NO) synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) and by deendothelialization. A fragment of ADM, ADM13-52, caused a degree of relaxation similar to that induced by ADM in pulmonary arterial rings, but not in the aortic rings, and the relaxation of pulmonary artery caused by ADM13-52 was not affected by the cyclooxygenase inhibitor indomethacin but was abolished by L-NAME and by deendothelialization. During hypoxia, ADM13-52 failed to relax pulmonary arterial rings, whereas ADM caused modest relaxation of pulmonary arterial rings (one third of the relaxation during normoxia), which was abolished by pretreatment with indomethacin. Our results indicate that the vasorelaxant effect of ADM is more pronounced in pulmonary artery than in the aorta; ADM has more potent vasodilator effect than ADM13-52 during hypoxia; ADM relaxes hypoxic pulmonary artery through an indomethacin-sensitive pathway; amino acids 1-12 in ADM must be present for relaxation of chronic hypoxic pulmonary arterial rings; and last, the presence of endothelium is necessary for the expression of ADM-mediated relaxation.


Effects of inspiratory muscle training on blood pressure- and sleep-related outcomes in patients with obstructive sleep apnea: a meta-analysis of randomized controlled trials.
Obstructive sleep apnea (OSA) is frequently accompanied by hypertension, resulting in cardiovascular comorbidities. Continuous positive airway pressure is a standard therapy for OSA but has poor adherence. Inspiratory muscle training (IMT) may reduce airway collapsibility and sympathetic output, which may decrease OSA severity and blood pressure. In this meta-analysis of randomized controlled trials (RCTs), we evaluated the efficacy of IMT in patients with OSA. We searched PubMed, EMBASE, Cochrane Library, Web of Science, and ClinicalTrials.gov databases for relevant RCTs published before November 2022. Seven RCTs with a total of 160 patients with OSA were included. Compared with the control group, the IMT group exhibited significantly lower systolic and diastolic blood pressure (mean difference [MD]: - 10.77 and - 4.58 mmHg, respectively), plasma catecholamine levels (MD: - 128.64 pg/mL), Pittsburgh Sleep Quality Index (MD: - 3.06), and Epworth Sleepiness Scale score (MD: - 4.37). No significant between-group differences were observed in the apnea-hypopnea index, forced vital capacity (FVC), ratio of forced expiratory volume in 1 s to FVC, or adverse effects. The data indicate comprehensive evidence regarding the efficacy of IMT for OSA. However, the level of certainty (LOC) remains low. IMT improved blood pressure- and sleep-related outcomes without causing adverse effects and may thus be a reasonable option for lowering blood pressure in patients with OSA. However, additional studies with larger sample sizes and rigorous study designs are warranted to increase the LOC.


Recent patents on ophthalmic nanoformulations and therapeutic implications.
Nanoformulations (NF) are widely explored as potential alternatives for traditional ophthalmic formulation approaches. The effective treatment of ocular diseases using conventional eye drops is often hampered by factors such as: physiological barriers, rapid elimination, protein binding, and enzymatic drug degradation. Combined, these factors are known to contribute to reduced ocular residence time and poor bioavailability. Recent research studies demonstrated that NF can significantly enhance the therapeutic efficacy and bioavailability of ocular drugs, compared to the established ophthalmic drug delivery strategies. The research studies resulted in a number of patent inventions, reporting a significant increase in therapeutic efficacy for various chronic ocular disease states of both the anterior and posterior ocular segments. This article reviews these patent disclosures in detail and emphasizes the therapeutic advantages conferred by the following nanoformulation approaches: Calcium Phosphate (CaP) nanoparticles, Liposomes, Nanoemulsions, Nanomicelles, and Hydrogels. The nanoformulation approaches were shown to enhance the ocular bioavailability by reducing the drugprotein binding, increasing the corneal resident time, enhancing the drug permeability and providing a sustained drug release. Further, the article discusses United States Food and Drug Administration (USFDA) approved ocular drugs employing nanotechnology and future developments. It should be noted that, despite the potential therapeutic promise demonstrated by nanotechnology for ocular drug delivery, the bench to bed transition from patent inventions to marketed drug products has been insignificant. Majority of the discussed technologies are still in development and testing phase for commercial viability. Further, studies are in progress to assess ocular tolerance and nanotoxicity for prolonged use of NF.


Pneumatonometry through bandage contact lenses.
Bandage soft contact lenses are an effective therapy for patients with a variety of corneal diseases. These patients often require accurate measurement of the intraocular pressure, necessitating movement or removal of the contact lens for slit-lamp Goldmann applanation tonometry. Intraocular pressure was measured in 21 normal, healthy volunteers, using a pneumatonometer (Alcon). A therapeutic soft contact lens (Plano T) was then placed on the eye and the pneumatonometer was used to remeasure the intraocular pressure through the contact lens. The average intraocular pressure without the contact lens was not statistically different from the intraocular pressure with the contact lens. These data suggest that pneumatonometry is an effective way to assess the intraocular pressure in patients wearing bandage contact lenses, thus eliminating the need to manipulate the lens solely for the purpose of intraocular pressure determination.


[Pancreatic fistula after left pancreatectomy. Risk factors analysis on 68 patients].
The aim of this study was to identify risk factors related to pancreatic fistula after left pancreatectomy, considering the difference between the use of mechanical suture and the manual suture to close the pancreatic stump. Sixty-eight patients, undergoing left pancreatectomy, were included in this study during a 10-year period. Eight possible risk factors related to pancreatic fistula were examined, such as demographic data (age and sex), pathology (pancreatic and extrapancreatic), technical characteristics (stump closure, concomitant splenectomy, additional procedures), texture of pancreatic parenchyma, octreotide therapy. Fourty-one patients (60%) underwent left pancreatectomy for primary pancreatic disease and 27 (40%) for extrapancreatic malignancy. Postoperative mortality and morbidity rates were 1.5% and 35%, respectively. Fourteen patients (20%) developed pancreatic fistula: 4 of them were classified as Grade A, 9 as Grade B and only one as Grade C. Three factors have been significantly associated to the incidence of pancreatic fistula: none prophylactic octreotide therapy, spleen preserving and soft pancreatic texture. It's still unclear the influence of pancreatic stump closure (stapler vs hand closure) in the onset of pancreatic fistula. In this study the incidence of pancreatic fistula after left pancreatectomy has been 20%. This rate is lower for patients with fibrotic pancreatic tissue, concomitant splenectomy and postoperative prophylactic octreotide therapy.


Comparative Functional Morphology of Human and Chimpanzee Feet Based on Three-Dimensional Finite Element Analysis.
To comparatively investigate the morphological adaptation of the human foot for achieving robust and efficient bipedal locomotion, we develop three-dimensional finite element models of the human and chimpanzee feet. Foot bones and the outer surface of the foot are extracted from computer tomography images and meshed with tetrahedral elements. The ligaments and plantar fascia are represented by tension-only spring elements. The contacts between the bones and between the foot and ground are solved using frictionless and Coulomb friction contact algorithms, respectively. Physiologically realistic loading conditions of the feet during quiet bipedal standing are simulated. Our results indicate that the center of pressure (COP) is located more anteriorly in the human foot than in the chimpanzee foot, indicating a larger stability margin in bipedal posture in humans. Furthermore, the vertical free moment generated by the coupling motion of the calcaneus and tibia during axial loading is larger in the human foot, which can facilitate the compensation of the net yaw moment of the body around the COP during bipedal locomotion. Furthermore, the human foot can store elastic energy more effectively during axial loading for the effective generation of propulsive force in the late stance phase. This computational framework for a comparative investigation of the causal relationship among the morphology, kinematics, and kinetics of the foot may provide a better understanding regarding the functional significance of the morphological features of the human foot.


Head stabilization during various locomotor tasks in humans. II. Patients with bilateral peripheral vestibular deficits.
This experiment, which extends a previous investigation (Pozzo et al. 1990), was undertaken to examine how head position is controlled during natural locomotor tasks in both normal subjects (N) and patients with bilateral vestibular deficits (V). 10 normals and 7 patients were asked to perform 4 locomotor tasks: free walking (W), walking in place (WIP), running in place (R) and hopping (H). Head and body movements were recorded with a video system which allowed a computed 3 dimensional reconstruction of selected points in the sagittal plane. In order to determine the respective contribution of visual and vestibular cues in the control of head angular position, the 2 groups of subjects were tested in the light and in darkness. In darkness, the amplitude and velocity of head rotation decreased for N subjects; these parameters increased for V subjects, especially during R and H. In darkness, compared to the light condition, the mean position of a line placed on the Frankfort plane (about 20-30 degrees below the horizontal semi-circular canal plane) was tilted downward in all conditions of movement, except during H, for N subjects. In contrast, this flexion of the head was not systematic in V subjects: the Frankfort plane could be located above or below earth horizontal. In V subjects, head rotation was not found to be compensatory for head translation and the power spectrum analysis shows that head angular displacements in the sagittal plane contain mainly low frequencies (about 0.3-0.8 Hz). The respective contribution of visual and vestibular cues in the control of the orientation and the stabilization of the head in space is discussed.


Medical management of early pregnancy failure: efficacy.
Early pregnancy failure is a common pregnancy complication. This article reviews the efficacy of medical management of early pregnancy failure. Nonsurgical treatments, including expectant and medical management, are reasonable alternatives to surgical management depending on the clinical situation and the patient's requests. Possible regimens in medical management of early pregnancy failure include misoprostol alone or mifepristone in conjunction with misoprostol. However, many studies of medical management may underestimate success rates due to inconsistent inclusion criteria, different dosing regimens, and varying definitions of failed treatment. Clinicians need to understand the range of efficacy of these regimens to provide appropriate counseling to patients.


Increased gamma-globin gene expression in beta-thalassemia intermedia patients correlates with a mutation in 3'HS1.
We report a novel set of genetic markers in the DNaseI hypersensitive sites comprising the human beta-globin locus chromatin hub (CH), namely HS-111 and 3'HS1. The HS-111 (-21 G>A) and 3'HS1 (+179 C>T) transitions form CH haplotypes, which occur at different frequencies in beta-thalassemia intermedia and major patients and normal (nonthalassemic) individuals. We also show that the 3'HS1 (+179 C>T) variation results in a GATA-1 binding site and correlates with increased fetal hemoglobin production in beta-thalassemia intermedia patients. In contrast, the HS-111 (+126 G>A) transition, found in three normal chromosomes, is simply a rare polymorphism. We conclude that the CH haplotypes are useful genetic determinants for beta-thalassemia major and intermedia patients, while the 3'HS1 (+179 C>T) mutation may have functional consequences in gamma-globin genes expression.


Peptides from Pisum sativum L. enzymatic protein digest with anti-adhesive activity against Helicobacter pylori: structure-activity and inhibitory activity against BabA, SabA, HpaA and a fibronectin-binding adhesin.
Identification of anti-adhesive peptides against Helicobacter pylori obtained by enzymatic hydrolysis of seed proteins from Pisum sativum L. (Fabaceae). Bioassay-guided fractionation of protein tryptic digest by ultrafiltration, size exclusion chromatography (SEC) and reversed phase chromatography (RPC) were used. Identification of bioactive peptides was achieved by MALDI-TOF-MS. Adhesion of H. pylori was monitored by two different assays, using a quantitative in vitro assay on human AGS cells with evaluation of bacterial binding by flow cytometry, beside a semi-quantitative in situ adhesion assay using FITC-labelled H. pylori on human stomach tissue sections. From two highly active fractions (F3, F3.3) two anti-adhesive peptides (S3, S5) were identified. Neither F3 nor S3 or S5 had any cytotoxic effect against H. pylori. By hemagglutination assay and semiquantitative dot blot overlay assay with immobilized ligands it was shown that F3 interacts specifically with H. pylori adhesins BabA, SabA, HpaA and a fibronectin-binding adhesin, while S3 and S5 inhibit only BabA. It was demonstrated that BabA, usually interacting with carbohydrate motifs such as fucosylated blood group antigens, interacts with the peptide moieties. Bioactive peptides from pea protein could be applied as functional ingredients for protecting infants and children against infections such as H. pylori.


Association between body image dissatisfaction and depressive symptoms in adolescents.
To determine the association between body image dissatisfaction (BID) and depressive symptoms in adolescents from a school in Lima, Peru. A cross-sectional study was performed through a census of 875 high-school students, aged 13 to 17 years, from a school in Lima. Participants completed a survey containing the Body Shape Questionnaire (BSQ) and the Patient Health Questionnaire-9 (PHQ-9). Data regarding demographics, alcohol and tobacco use, self-esteem, and family history of depression were also obtained. To identify associated factors, Poisson regression with robust variance was used. Prevalence ratios with 95% confidence intervals were calculated. Of the 875 adolescents, 55.8% were male. The mean age was 14.1±1.5 years. Depressive symptoms were observed in 19.9% of participants. An association between BID and depressive symptoms was found. Alcohol and tobacco use were also associated with the outcome of interest. Teens who had BID were 3.7 times more likely to report depressive symptoms. Additionally, those who used tobacco or alcohol were 1.5 and 1.4 times more likely to have depressive symptoms, respectively. Further studies targeting other populations and using longitudinal designs are recommended.


Teledermatology: the case of adoption and diffusion of telemedicine health Waikato in New Zealand.
Telemedicine emerged as a possible solution to New Zealand health providers in reaching out to rural patients, by offering medical services and conducting administrative meetings and training. However, despite the rapid growth and high visibility of these projects in countries like the United States, relatively few patients are now being seen through telemedicine. Accordingly, this research attempts to investigate telemedicine's effectiveness in New Zealand by using a theoretical framework. Thus, the purpose of this paper is to explain factors influencing the adoption and diffusion of telemedicine utilising the video conferencing technology (TMVC) for dermatology within Health Waikato Ltd. (HW). Findings indicate weak presence of critical assessment into technological innovation prior to adoption. Factors like complexity, compatibility, and trialability were not assessed extensively by HW, and would have hindered its adoption. Teledermatology was mainly assessed according to its relative advantage and cost effectiveness. While essential this should be alongside other factors pertaining to as addressed within this research. On the other hand, the wide diffusion of teledermatology relied on its economical benefit to HW and on its effectiveness as a diagnostic tool. This research highlights the importance of the product champion for the successful adoption and diffusion of teledermatology.


Burden of smoking on cause-specific mortality: application to the Nurses' Health Study.
The burden of smoking on six causes of death in women was evaluated using various novel modelling approaches. A prospective US-based nationwide cohort study. 102 635 women in the Nurses' Health Study followed biennially from 1980 to 2004. The relation between cigarette smoking and cause-specific death was compared using baseline versus biennially updated smoking status. The authors used competing risk survival analysis to formally compare associations of smoking-related variables on risk of death as a result of coronary heart disease (CHD), cerebrovascular diseases, lung cancer, other respiratory diseases, other smoking-caused cancers and other causes. The associations of current and former smoking were stronger with most cause-specific mortality when using updated information. The effect of each smoking-related variable differed significantly (p(h) <0.0001) across some causes of death. For example, risks increased by 5% for death due to other causes up to 37% for lung cancer death for a 5-year earlier age at initiation. Compared with continuing to smoke, former smokers with 5-10 years of cessation had a 25% reduction in risk of dying from other causes of death up to a 61% reduction in risk of dying from CHD and cerebrovascular diseases. The risks of smoking and the benefits from quitting are greater than previously reported, when utilising repeated measures of smoking data collected during follow-up, and vary by cause of death. Focused efforts to communicate the benefits of quitting to smokers and to prevent smoking initiation among children and youths should remain top public health priorities to reduce the worldwide mortality burden caused by smoking.


Anticoagulation Therapy for Atrial Fibrillation in Patients With Alzheimer's Disease.
Background and Purpose- Direct oral anticoagulants (DOACs) are safer, at least equally efficacious, and cost-effective compared to warfarin for stroke prevention in atrial fibrillation (AF) but they remain underused, particularly in demented patients. We estimated the cost-effectiveness of DOACs compared with warfarin in patients with AF and Alzheimer's disease (AD). Methods- We constructed a microsimulation model to estimate the lifetime costs, quality-adjusted life-years (QALYs), and cost-effectiveness of anticoagulation therapy (adjusted-dose warfarin and various DOACs) in 70-year-old patients with AF and AD from a US societal perspective. We stratified patient cohorts based on stage of AD and care setting. Model parameters were estimated from secondary sources. Health benefits were measured in the number of acute health events, life-years, and QALYs gained. We classified alternatives as cost-effective using a willingness-to-pay threshold of $100 000 per QALY gained. Results- For patients with AF and AD, compared with warfarin, DOACs increase costs but also increase QALYs by reducing the risk of stroke. For mild-AD patients living in the community, edoxaban increased lifetime costs by $6603 and increased QALYs by 0.076 compared to warfarin, yielding an incremental cost-effectiveness ratio of $86 882/QALY gained. Even though DOACs increased QALYs compared with warfarin for all patient groups (ranging from 0.019 to 0.085 additional QALYs), no DOAC treatment alternative had an incremental cost-effectiveness ratio <$150 000/QALY gained for patients with moderate to severe AD. For patients living in a long-term care facility with mild AD, the DOAC with the lowest incremental cost-effectiveness ratio (rivaroxaban) costs $150 169 per QALY gained; for patients with more severe AD, the incremental cost-effectiveness ratios were higher. Conclusions- For patients with AF and mild AD living in the community, edoxaban is cost-effective compared with warfarin. Even though patients with moderate and severe AD living in the community and patients with any stage of AD living in a long-term care setting may obtain positive clinical benefits from anticoagulation treatment, DOACs are not cost-effective compared with warfarin for these populations. Compared to aspirin, no oral anticoagulation (warfarin or any DOAC) is cost effective in patients with AF and AD.