Preparation Of 2′-Hydrazino Oligonucleotides And Their Reaction With Aldehydes And 1,3-Diketones

Oligodeoxyribonucleotides that contain a hydrazino nucleoside, 2′-O-(2-hydrazinoethyl)uridine were prepared and shown to react with aldehydes or 1,3-diketones with the formation of hydrazones or pyrazoles, respectively. The method may be applicable for the preparation of oligonucleotide-peptide conjugates.     

Dose‐ And Administration Time‐Dependent Effects Of Nifedipine Gits On Ambulatory Blood Pressure In Hypertensive Subjects

Previous chronotherapy studies have shown that the circadian pattern of blood pressure (BP) remains unchanged after either morning or evening dosing of several calcium channel blockers (CCB), including amlodipine, isradipine, verapamil, nitrendipine, and cilnidipine. This trial investigated the antihypertensive efficacy and safety profile of the slow‐release, once‐a‐day nifedipine gastrointestinal therapeutic system (GITS) formulation administered at different times with reference to the rest‐activity cycle of each participant. We studied 80 diurnally active subjects (36 men and 44 women), 52.1±10.7 yrs of age, with grade 1–2 essential hypertension, who were randomly assigned to receive nifedipine GITS (30 mg/day) as a monotherapy for eight weeks, either upon awakening in the morning or at bedtime at night. Patients with uncontrolled BP were up‐titrated to a higher dose, 60 mg/day nifedipine GITS, for an additional eight weeks. BP was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours before and after therapy with either dose. The BP reduction after eight weeks of therapy with the lower dose of 30 mg/day was slightly, but not significantly, larger with bedtime dosing. The efficacy of 60 mg/day nifedipine GITS in non‐responders to the initial 30 mg/day dose was twice as great with bedtime as compared to morning dosing. Moreover, bedtime administration of nifedipine GITS reduced the incidence of edema as an adverse event by 91%, and the total number of all adverse events by 74% as compared to morning dosing (p=0.026). Independent of the time of day of administration, a single daily dose of 30 mg/day of nifedipine GITS provides full 24 h therapeutic coverage. The dose‐dependent increased efficacy and the markedly improved safety profile of bedtime as compared to morning administration of nifedipine GITS should be taken into account when prescribing this CCB in the treatment of essential hypertension.     

Reconstitution Of β-catenin Degradation In Xenopus Egg Extract

Xenopus laevis egg extract is a well-characterized, robust system for studying the biochemistry of diverse cellular processes. Xenopus egg extract has been used to study protein turnover in many cellular contexts, including the cell cycle and signal transduction pathways^1-3. Herein, a method is described for isolating Xenopus egg extract that has been optimized to promote the degradation of the critical Wnt pathway component, β-catenin. Two different methods are described to assess β-catenin protein degradation in Xenopus egg extract. One method is visually informative ([³⁵S]-radiolabeled proteins), while the other is more readily scaled for high-throughput assays (firefly luciferase-tagged fusion proteins). The techniques described can be used to, but are not limited to, assess β-catenin protein turnover and identify molecular components contributing to its turnover. Additionally, the ability to purify large volumes of homogenous Xenopus egg extract combined with the quantitative and facile readout of luciferase-tagged proteins allows this system to be easily adapted for high-throughput screening for modulators of β-catenin degradation.     

Does Clinical Inertia Vary By Personalized A1C Goal? A Study Of Predictors And Prevalence Of Clinical Inertia In A U.S. Managed Care Setting

Objective: Clinical inertia is defined as failure to initiate or intensify therapy despite an inadequate treatment response. We assessed the prevalence and identified the predictors of clinical inertia among patients with type 2 diabetes (T2DM) based on personalized goals.Methods: Three hemoglobin A_1c (A1C) targets (American Diabetes Association A1C <7.0%; modified Ismail-Beigi et al; and Healthcare Effectiveness Data and Information Set) were used when identifying adult patients with T2DM who experienced above-target A1C values during the index period (July 1, 2008 to June 30, 2012) in a U.S. managed-care claims database (IMPACT™). Clinical inertia was defined as no intensification of treatment during the response period. Demographic and clinical characteristics were analyzed to identify predictors of treatment intensification.Results: Irrespective of A1C target, the majority of patients with T2DM (70.4 to 72.8%) experienced clinical inertia in the 6 months following the index event, with 5.3 to 6.2% of patients intensifying treatment with insulin. Patients with a lower likelihood of intensification were older, used >1 oral antidiabetes drug during the baseline period, and had an above-target A1C more recently. Treatment intensification was associated with patients who had point-of-service insurance, mental illness, an endocrinologist visit in the baseline period, or higher index A1C.Conclusion: The prevalence of clinical inertia among patients with T2DM in a U.S. managed-care setting is high and has increased over more recent years. Factors predicting increased risk of clinical inertia may help identify “at-risk” populations and assist in developing strategies to improve their management.Abbreviations:A1C = hemoglobin A_1cADA = American Diabetes AssociationCCI = Charlson Comorbidity IndexGLP-1 = glucagon-like peptide 1HEDIS = Healthcare Effectiveness Data and Information SetICD-9-CM = International Classification of Diseases, 9th Revision, Clinical ModificationOAD = oral antidiabetes drugPCPs = primary care physiciansT2DM = type 2 diabetes mellitus     

Studying The Right Cell In Acute Myelogenous Leukemia: Dynamic Changes Of Apoptosis And Signal Transduction Pathway Protein Expression In Chemotherapy Resistant Ex-Vivo Selected “Survivor Cells”

We hypothesized that studying protein expression in cells surviving in vitro chemotherapy (“survivor cells”, SV), could provide more important insight into the biology of drug-resistant AML cells than analysis of the bulk population of leukemic cells. Leukemia-enriched samples from 79 patients with new or relapsed AML were cultured for 4 days ± cytarabine (5-10 μM). Early apoptotic cells were removed to yield purified SV. Expression of BCL2, bax, PKCα, ERK2, and pERK2 proteins was measured using laser scanning cytometry. The SV population was enriched for CD34+ stem cells. Protein expression patterns in SV differed considerably from those in controls; culture and reanalysis of protein expression revealed stability, reversion, or new patterns of change. Patterns of pairs or triads of proteins were nonrandomly distributed and appeared at statistically unlikely frequencies, suggesting preferential adoption of certain patterns. The patterns of change were highly predictive of remission attainment, relapse, and survival in univariate and multivariate analysis. We conclude that in vitro SV cells have protein expression patterns distinct from those of the bulk population of leukemic cells and that these patterns are predictive of outcome. Analysis of SV cells may be more informative than analysis of the bulk population of leukemia cells.     

God’S Laboratory: Religious Rationalities And Modernity In Ecuadorian In Vitro Fertilization

Catholicism is the only major world religion that unequivocally bans the use of in vitro fertilization (IVF). Nevertheless, in Ecuador, Catholic IVF practitioners declare God’s dominion over their IVF laboratories and clinics in explaining pregnancy outcomes. My analysis of this routine combination of spiritual and material causal models in Ecuadorian IVF contributes to two ongoing discussions about (1) the tensions between “institutional” and popular forms of Catholic religiosity and (2) the proper boundaries of science in modernity. The Catholic Church’s historical and contemporary struggle to determine control of the miraculous has usually been characterized as a conflict between educated clergy and humble peasants. In the case of Ecuadorian IVF, we find, instead, educated elites and middle classes participating in this same contestation with the Church, proclaiming their direct ability to harness the power of God to effect material change on earth. This spiritual power to affect clinical outcomes does not take place just anywhere, but in clinic and lab, disrupting another set of presumptions about modern scientific practice and subjectivity. Like other Ecuadorian elites and middle classes, IVF practitioners are heirs to Enlightenment thought, and experience themselves as modern in their participation in these high-tech endeavors. But their spiritual approach to laboratory rationality does not trouble these IVF practitioners’ experience of themselves as moderns, prompting a reevaluation of the narratives of scientific modernity that limit their scope to Europe and North America.     

Climate,Acculturation, And Costume A History Of Women’S Clothing Among The Indians Of The Southern Plains

Abstract

This paper accepts Clark Wissler’s dictum, offered as long ago as 1915, in his pioneer study of Plains Indian clothing, that for such perishable objects as costume “real historic data is usually available.” Applying a combination of evidence provided by dated, first-hand, written observations, early drawings and later photographs, as well as selected well documented specimens preserved in museum collections to a study of historic Southern Plains Indian women’s body costume one finds that south of the northern limit of 180 frost-free days the prevailing women’s attire prior to the mid-19th century was a skin skirt and a poncho of the same material. In warm weather the poncho was often omitted sometimes exposing a wearer’s profusely painted or tattooed mammae. By the 1820s some women of affluent families made their garments of trade cloth. By the 1850s a long, trade cloth dress, with kimono sleeves and inset gores was becoming fashionable. This garment, in turn, was superceded among women of status by a three piece skin dress after buckskin became relatively scarce. The two piece skin dress which Wissler proposed as the “plains style” was never typical of the tribes of the Southern Plains. Rather the evidence argues against culture area uniformity in women’s clothing, while suggesting that climate and acculturation resulting from white contact strongly influenced a variety of dress styles among the women of the plains tribes. Indeed the body garments worn by women on the Southern Plains prior to 1850 strikingly resemble those depicted on classic figurines from Vera Cruz, Mexico, while they differed totally from garments worn by women of Northern Plains tribes during early historic times.     

First Synthesis And Antimicrobial Activity Of N- and S-α-L-Arabinopyranosyl-1,2,4-Triazoles

Arabinosylation of some 4-amino- and 4-arylideneamino-5-(pyridin-3-yl)-2,4-dihydro-[1,2,4]-triazole-3-thiones with 2,3,4-tri-O-acetyl-β-L-arabinopyranosyl bromide led to an efficient synthetic approach to the corresponding N-and S-α-L-arabinopyranosides. Structure assignment of these two regiosiomers was based on chemical and spectroscopic evidences. Antimicrobial activities of two selected regioisomeric N-and S-α-L-arabinopyranosides were compared. The N-α-L-arabinopyranoside showed higher inhibitory effect than its regioisomeric S-α-L-arabinopyranoside against Aspergillus fumigatus, Penicillium italicum, Staphylococcus aureus, and Pseudomonas aeruginosa.     

Translation And Cultural Adaptation Of A Mental Health Outcome Measure: The Basis-R©

Culturally and linguistically appropriate outcome measures are needed to address the needs of Latino consumers of mental health services. The revised Behavior and Symptom Identification Scale (BASIS-R(c)) is an English-language consumer self-report measure designed to assess outcome of behavioral health or substance abuse treatment. This study sought to develop a culturally and linguistically appropriate version of the BASIS-R(c) for Spanish-speaking Latinos. To achieve this goal, the English instrument was translated and adapted into Spanish by an international bilingual committee and tested in four focus groups and 45 cognitive interviews with Puerto Ricans, Dominicans, and Mexicans living in the United States and Puerto Rico. Focus groups and cognitive interviews provided qualitative and quantitative information about the instrument's content and format, and respondents' understanding of the instructions, questionnaire items, time frame, and response options. Respondents' ratings of the clarity and importance of each item were also obtained. Analyses of focus group and cognitive interview data identified items that were confusing or difficult for participants. Findings suggest that the Spanish version of the BASIS-R(c) incorporated the cultural diversity of the three groups of Latinos in this study without compromising the validity of the English version of the BASIS.     

Sequence Variation Of the α-Lactalbumin Gene In Holstein and Nellore Cows

The α-lactalbumin is a subunit of lactose-synthase, an enzyme responsible for lactose production, a disaccharide that influences milk production. Sequence variations of bovine α -lactalbumin have been associated with differences in milk yield. This study aimed to analyze allelic frequency differences at position ? 1689 (g. A > G) and + 15 (g. A > G) of the α-lactalbumin gene in Holstein (Bos taurus) and Nellore (Bos indicus) cows. Blood samples were analyzed from 34 Holstein, 104 Nellore, and 99 Dairy Nellore cows using PCR-RFLP. The different RFLP patterns were sequenced and a novel sequence variation on nucleotide ? 46 was identified. An adenine at this position was designated as the A allele and a guanine was designated B allele. The frequencies of alleles A ? 1689, A ? 46, and A + 15 differed between Holstein and both Nellore breeds. The results show that differences in α-lactalbumin allelic variants in the 5′-flanking and the 5′-UTR region might be associated with differences in milk production between Holstein cows and cows from Nellore breeds. However, the lack of difference between Nellore and Dairy Nellore suggests that other sequence variantions that regulate milk production might be responsible for the selection of Dairy Nellore cows with superior milk production.     

The Landscape Of Alpha Fetoprotein In Hepatocellular Carcinoma: Where Are We?

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has been acknowledged as a leading cause of death among cirrhosis patients. Difficulties in early diagnosis and heterogeneity are obstacles to effective treatment, especially for advanced HCC. Liver transplantation (LT) is considered the best therapy for HCC. Although many biomarkers are being proposed, alpha-fetoprotein (AFP), which was identified over 60 years ago, remains the most utilized. Recently, much hope has been placed in the immunogenicity of AFP to develop novel therapies, such as AFP vaccines and AFP-specific adoptive T-cell transfer (ACT). This review summarizes the performance of AFP as a biomarker for HCC diagnosis and prognosis, as well as its correlation with molecular classes. In addition, the role of AFP in LT is also described. Finally, we highlight the mechanism and application prospects of two immune therapies (AFP vaccine and ACT) for HCC. In general, our review points out the prevalence of AFP in HCC, accompanied by some controversies and novel directions for future research.     

Consensus Statement By The American Association Of Clinical Endocrinologists And American College Of Endocrinology On The Comprehensive Type 2 Diabetes Management Algorithm – 2016 EXECUTIVE SUMMARY

Abbreviations:A1C = hemoglobin A1CAACE = American Association of Clinical EndocrinologistsACCORD = Action to Control Cardiovascular Risk in DiabetesACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood PressureACEI = angiotensinconverting enzyme inhibitorAGI = alpha-glucosidase inhibitorapo B = apolipoprotein BARB = angiotensin II receptor blockerASCVD = atherosclerotic cardiovascular diseaseBAS = bile acid sequestrantBMI = body mass indexBP = blood pressureCHD = coronary heart diseaseCKD = chronic kidney diseaseCVD = cardiovascular diseaseDKA = diabetic ketoacidosisDPP-4 = dipeptidyl peptidase 4EPA = eicosapentaenoic acidFDA = Food and Drug AdministrationGLP-1 = glucagon-like peptide 1HDL-C = high-density-lipoprotein cholesterolLDL-C = low-densitylipoprotein cholesterolLDL-P = low-density-lipoprotein particleLook AHEAD = Look Action for Health in DiabetesNPH = neutral protamine HagedornOSA = obstructive sleep apneaSFU = sulfonylureaSGLT-2 = sodium glucose cotransporter-2SMBG = self-monitoring of blood glucoseT2D = type 2 diabetesTZD = thiazolidinedione     

The Structure And Synthetic Capabilities Of A Catalytic Peptide Formed By Substrate-Directed Mechanism – Implications To Prebiotic Catalysis

Previously, we have shown that a small substrate may serve as a template in the formation of a specific catalytic peptide, a phenomenon which might have had a major role in prebiotic synthesis of peptide catalysts. This was demonstrated experimentally by the formation of a catalytic metallo-dipeptide, Cys₂-Fe²⁺, around o-nitrophenyl β-D-galactopyranoside (ONPG), by dicyandiamide (DCDA)-assisted condensation under aqueous conditions. This dipeptide was capable of hydrolyzing ONPG at a specific activity lower only 1000 fold than that of β galactosidase. In the present paper we use molecular modeling techniques to elucidate the structure of this catalyst and its complex with the substrate and propose a putative mechanism for the catalyst formation and its mode of action as a “mini enzyme”. This model suggests that interaction of Fe²⁺ ion with ONPG oxygens and with two cysteine SH groups promotes the specific formation of the Cys₂-Fe²⁺ catalyst. Similarly, the interaction of the catalyst with ONPG is mediated by its Fe²⁺ with the substrate oxygens, leading to its hydrolysis. In addition, immobilized forms of the catalyst were synthesized on two carriers – Eupergit C and amino glass beads. These preparations were capable of catalyzing the formation of ONPG from β-D-galactose and o-nitrophenol (ONP) under anhydrous conditions. The ability of the catalyst to synthesize the substrate that mediates its own formation creates an autocatalytic cycle where ONPG catalyzes the formation of a catalyst which, in turn, catalyzes ONPG formation. Such autocatalytic cycle can only operate by switching between high and low water activity conditions, such as in tidal pools cycling between wet and dry environments. Implications of the substrate-dependent formation of catalytically active peptides to prebiotic processes are discussed     

Hyperinsulinemia Associated With Acanthosis Nigricans,Finger Pebbles,Acrochordons, And The Sign Of Leser-Trélat

ObjectiveTo review common skin manifestations associated with type 2 diabetes mellitus (DM), and to discuss a potential underlying mechanism for these manifestations.MethodsA PubMed literature search was conducted for articles describing the skin manifestations associated with hyperinsulinemia and type 2 DM. A case presentation describes a morbidly obese patient with type 2 DM treated with metformin who developed acanthosis nigricans, finger pebbles, scores of skin tags (acrochordons), and the sign of LeserTrelat (sudden onset shower of seborrheic keratoses) in the absence of internal malignancy.ResultsAcanthosis nigricans, acrochordons, and finger pebbles have been associated with type 2 DM and obesity. While the LeserTrelat sign is classically associated with internal malignancy, it can also be idiopathic. To our knowledge, this the first report of the occurrence of the LeserTrelat sign in a patient with DM absent internal malignancy.ConclusionSeveral skin manifestations can be seen in this patient with DM because of underlying insulin resistance and subsequent stimulation of insulinlike growth factor receptors. Management strategies could include weight loss, diet, and insulinsensitizing pharmacologic therapy. (Endocr Pract. 2013;19:522525)     

New Neplanocin Analogues. V. A Potent Adenosylhomocysteine Hydrolase Inhibitor Lacking Antiviral Activity. Synthesis And Antiviral Activity Of 6″-Carboxylic Acid Derivatives Of Neplanocin A 1

Abstract

The 6′-carboxylic acid derivative of neplanocin A 3 was synthesized from NPA, and was converted to the corresponding methyl ester 4 and amides 5 and 6. These were evaluated for their anti-RNA-virus activities. Of the derivatives synthesized, only 5 was active against RNA viruses within the concentration range of 0.14-4.88 μg/mL. Compounds 3 and 5 showed a potent inhibitory effect on S-adenosylhomocysteine (AdoHcy) hydrolase from rabbit erythrocytes. Although a close correlation between the inhibitory effect of adenosine analogues on AdoHcy hydrolase and their antiviral potency has been demonstrated, 3 did not show any anti-RNA-virus activities.

     

Interobserver And Intraobserver Agreement In Parathyroid Scintigraphy: How Can Parathyroid Scintigraphy Be Made More Reliable?

ObjectiveTo determine the intraobserver and interobserver agreement levels in the evaluation of technetium Tc 99m sestamibi parathyroid scintigraphic images.MethodsNinety-eight patients with hyperparathyroidism were included in the study, and their parathyroid images were evaluated by 4 experienced nuclear medicine observers. The 98 cases were evaluated twice by each observer within an interval of 2 weeks. The evaluations were performed directly on workstations with use of digital images. A questionnaire was completed by each observer. The presence of a lesion, the number and the localizations of the lesions, and whether the lesion was clear or doubtful were all evaluated. Cohen kappa statistics and total agreement percentages were calculated by using SPSS version 11.0 software.ResultsThe 4 observers performed 8 different evaluations and identified a minimum of 38 and a maximum of 43 cases with a parathyroid lesion (or lesions). Both the intraobserver and the interobserver agreements were “very good” for the presence of a parathyroid lesion. The intraobserver agreement was also “very good” and the interobserver agreement was “good” (for only 1 pair of observers) or “very good” for the evaluation of the number of parathyroid lesions. The intraobserver agreement was “very good” or “good” and the interobserver agreement was “good” for the lesion localization and for the presence of a doubtful lesion.ConclusionParathyroid scintigraphy seems to be an observer independent method in the detection of a parathyroid lesion, in the determination of the number of lesions, and in the localizations of the lesions. The measured high agreement between observers increases the reliability of parathyroid scintigraphy. (Endocr Pract. 2012;18: 538-548)     

The Use Of Lead Tetraacetate,Benzidine, O-Dianisidine and A “Film Test” In Investigating The Periodic-Acid-Schiff Technic

In order to obtain a better understanding of the “periodic-acid-Schiff” reaction, also known as the “periodic-acid fuchsin-sulfurous-acid” reaction, three types of investigations were carried out

1) The Schiff reagent was replaced by other aldehyde reagents: benzidine or o-dianisidine. There was no significant change in the histological distribution and intensity of the reactions occurring after periodic acid oxidation.

2) Periodic acid was replaced by another oxidizing agent: lead tetraacetate (dissolved in acetic acid). There was no significant change in the histological distribution of the reactions with the Schiff reagent, but some change in their intensity. It was concluded that 1,2-glycols and a-amino alcohols play the main role in the reactions with both oxidants. The presence of α-hydroxy acids in some types of mucous cells is suggested by the results with lead tetraacetate.

Incidently, glycogen and starch are not sufficiently oxidized by lead tetraacetate (in acetic acid) at room temperature to give positive reactions with the Schiff reagent, while cellulose and other periodic-acid-Schiff reactive substances are.

3) The staining of films of presumed reactive substances with the periodic-acid-Schiff technic C O the intense reactivity of many polysaccharides, mucopolysaccharides and mucoproteins, but not of ordinary proteins. (Hyaluronic and chondroitin sulfuric acid are, however, not reactive in vitro).

In conclusion, the periodic-acid-Schiff technic consists of an oxidation of 1,2-glycols and a-amino alcohols to produce aldehyde groups, which are then stained by the Schiff reagent. The “film test” reveals that these radicals are present in certain polysaccharides, mucopolysaccharides and mucoproteins.