Miracle-dz/UniFAR-FTUs huggingface dataset:
Correlation of Toxicity and Pharmacokinetic Properties of a Phosphorothioate Oligonucleotide Designed to Inhibit ICAM-1

ISIS 2302 is a phosphorothioate oligodeoxynucleotide with a sequence complementary to the mRNA of human intercellular adhesion molecule 1 (ICAM-1). Hybridization of ISIS 2302 to the mRNA inhibits expression of the ICAM-1 protein in response to inflammatory stimuli. A murine active antisense oligonucleotide, ISIS 3082, has been used for in vivo pharmacology studies and has anti-inflammatory activity in models of organ transplant rejection, ulcerative colitis, and collagen-induced arthritis at doses ranging from 0.03 to 5 mg/kg. The safety assessment for ISIS 2302 includes general toxicity studies up to 6 mo in duration in mice and monkeys, genetic toxicity studies, and reproductive/fertility studies. ISIS 3082 was examined in parallel with ISIS 2302 in mouse toxicity and reproductive studies. The toxicities observed following systemic administration of ISIS 2302 and ISIS 3082 were similar and consistent with those observed for other compounds in this chemical class and, therefore, are independent of the suppression of ICAM-1 expression. Toxicokinetic evaluation demonstrated that toxicities occurred in organs containing the highest concentrations of ISIS 2302. Evidence of immune stimulation, including dose-dependent splenomegaly, lymphoid hyperplasia, and multiorgan mixed mononuclear cell infiltrates, was the most common finding in rodent studies. Monkeys were much less sensitive than mice to immune stimulation. Kidney contained the highest concentrations of ISIS 2302. Morphologic changes observed in kidney included atrophic and regenerative changes in proximal tubular epithelium; however, there was no evidence of functional abnormalities. Additional histologic changes noted in proximal tubular epithelium included basophilic granules, which were reflective of oligonucleotide distribution and uptake in these cells. Liver also contained high concentrations of oligonucleotide, which were associated with Kupffer cell hypertrophy in mice. Changes in serum transaminases, cholesterol, and triglycerides were reflective of hepatic alterations. In monkeys, high concentrations of oligonucleotide caused a transient increase in clotting times and activation of the alternative complement pathway. All toxicities associated with ISIS 2302 were reversible and occurred at doses well above those required for pharmacologic activity or currently used in clinical trials. In addition, there has been no evidence of genetic toxicity associated with ISIS 2302, and no changes in reproductive performance, fertility, or fetal development have been noted in animals treated with ISIS 2302 or ISIS 3082.
A pilot study on the effects of a polyherbal formulation cream on diabetic foot ulcers

Background & objectives: Diabetic foot ulcers are the most common cause of non-traumatic lower extremity amputations in developing countries. The aim of this pilot study was to evaluate the safety of using a polyherbal formulation in healing diabetic foot ulcers in comparison with standard silver sulphadiazine cream among patients with type 2 diabetes. Methods: A total of 40 (M:F=29:14) consecutive type 2 diabetes patients with foot ulcers were enrolled in this study. They were randomly assigned to two groups of 20 each; Group 1 was treated with polyherbal formulation and group 2 with silver sulphadiazine cream. All the patients were followed up for a period of 5 months. The baseline ulcer size was noted and photograph of the wound was taken at the baseline and at each follow up visit. Number of days taken for healing of the wound was recorded. Results: The mean age of patients, duration of diabetes and HbA1c% were similar in both the study groups. The mean length and width of the ulcers was also similar in both the groups at baseline visit. There was a significant decrease in the size of the wound (length and width) in both the study groups (P<0.001). The mean time taken for the healing of the ulcer was around 43 days in both groups. Interpretation & conclusions: Diabetic wound cream prepared by using polyherbal formulation was found to be effective as well as safe in healing diabetic foot ulcers like the standard silver sulphadiazine cream.
Respiratory Hazards in the Premature Infant

At birth the newborn infant is required to make an abrupt adjustment to a new environment. Hitherto its existence has been parasitic and its needs have been supplied by the maternal organism. The most immediate dramatic changes required to support extra uterine life are concerned with respiration and the circulation. The infant must achieve a regular respiratory rhythm and be able to expand its lungs fully. At the same time the blood flow through the pulmonary circulation must be adequate for the gaseous exchange to take place between the pulmonary capillaries and the lumen of the air spaces. The necessary adjustment is not achieved without difficulty in some mature infants and is an infinitely more serious problem for the premature infant. Any definition of prematurity has its drawbacks, but the most generally accepted criterion is a birth weight of under 2,500 g. It is to be remembered that twins will be more advanced in their development than their birth weight would suggest and that certain races, such as the negroes, are more mature at a given weight than the white races. Morrison (1952) states that 50 per cent. of all twins are under 2,500 g. at birth. The premature infant is a much more puny specimen than is the offspring of a full-term pregnancy. It has a greater surface area in relation to its body weight and so tends to lose heat and fluid more easily. It has little subcutaneous fat and so its insulation is poor. Furthermore, the cause of prematurity may have some bearing on its chances of survival. Pre-eclamptic toxaemia, ante-partum haemorrhage and rhesus iso-immunization of the mother may result in premature delivery. The first two disorders often result in the infant being severely affected by anoxia and the third causes the infant to be affected with haemolytic disease. Other maternal diseases, such as cardiac disease, tuberculosis and diabetes mellitus, may prevent the pregnancy from going to term and the infant suffers beyond the customary hazards of a premature delivery. In many cases, perhaps as many as 40 per cent. , there is no apparent cause for the interruption of pregnancy, and the infant is delivered in a healthy state, but is immature. It now has to assume an independent existence, and good respiratory function is vital. Unsatisfactory respiratory function is responsible for 15 per cent. of deaths among premature infants, according to Keeri-Szanto et al. (1950). Among the very premature infants, 750-1,000 g. birth weight, Potter (1952) found that respiratory failure was responsible for death in 85 per cent. At Queen Charlotte's Hospital we have found that respiratory dysfunction was at least partly responsible for the death of I44 (72 per cent.) of 193 premature infants of all ranges of birth weight from 700-2,500 g. Satisfactory respiratory function depends on the adequacy of the central nervous system, lungs and respiratory muscles and on the absence of pathological changes which are likely to affect respiration.
Surgical management of bronchopulmonary carcinoids: A single center experience

Abstract Introduction: Bronchopulmonary carcinoids are uncommon tumors with relatively indolent biological behavior but a distinct malignant potential. Surgery is the mainstay of treatment. Our aim was to study preoperative characteristics, surgical approaches, and outcome in patients with bronchopulmonary carcinoid tumors. Patients and Methods: This retrospective study was done in the Department of Surgical Oncology of a Tertiary Teaching Hospital of North India. The case records of all the patients who underwent surgical treatment for lung neoplasms and were diagnosed to have bronchopulmonary carcinoids were reviewed. Details concerning the clinical presentation, preoperative therapy, operative procedure, postoperative complications, and outcome were retrieved from the case records. Results: Sixteen patients who underwent surgical treatment were found to have bronchopulmonary carcinoids on histopathological examination. The median age of the patients was 34 years (range 18–62 years). There were 11 men and five women. All patients were symptomatic, and the median duration of symptoms was 12 months (range 6–72 months) before presentation. Six patients had received antitubercular treatment before presentation, and one patient had been treated with chemotherapy due to misdiagnosis. Surgical procedures included six pneumonectomies (one with carinoplasty), four bilobectomies, three lobectomies, and three bronchoplastic procedures (two with lobectomy and one with bilobectomy). There was no postoperative mortality; three patients had morbidity in the form of lobar collapse, prolonged pleural collection, and surgical site infection. With a median follow-up time of 11 months (range 2–85 months), all the 16 patients are alive and disease-free. Conclusions: Delayed presentation and misdiagnosis of bronchial carcinoid are major concerns in North India. Adequate surgical resection can be performed without undue morbidity and is associated with good long-term results.
Male menopause: is it a real clinical syndrome?

The association between aging-related testosterone deficiency and late-onset clinical hypogonadism in men remains a controversial concept. Several descriptive names, such as andropause, male menopause, partial androgen deficiency of the aging male and late-onset hypogonadism, have been suggested in an attempt to connect the age-related decline in androgen production and symptoms of aging in men. However, despite many studies, no clear correlation has been established and, as a result, there is also a debate over the use of androgen replacement therapy in this clinical set-up. Nevertheless, new data from large-scale studies have been recently published, which shed more light on this complicated issue. A recent New England Journal of Medicine article demonstrated that only a minor fraction (2%%) of elderly men suffer from this clinical syndrome and gave serum testosterone level thresholds that support it.
Aspartyl β-Hydroxylase (Asph) and an Evolutionarily Conserved Isoform of Asph Missing the Catalytic Domain Share Exons with Junctin*

The mouse aspartyl β-hydroxylase gene (Asph, BAH) has been cloned and characterized. The mouseBAH gene spans 200 kilobase pairs of genomic DNA and contains 24 exons. Of three major BAH-related transcripts, the two largest (6,629 and 4,419 base pairs) encode full-length protein and differ only in the use of alternative polyadenylation signals. The smallest BAH-related transcript (2,789 base pairs) uses an alternative 3′ terminal exon, resulting in a protein lacking a catalytic domain. Evolutionary conservation of this noncatalytic isoform of BAH (humbug) is demonstrated in mouse, man, andDrosophila. Monoclonal antibody reagents were generated, epitope-mapped, and used to definitively correlate RNA bands on Northern blots with protein species on Western blots. The gene for mouse junctin, a calsequestrin-binding protein, was cloned and characterized and shown to be encoded from the same locus. When expressed in heart tissue, BAH/humbug preferably use the first exon and often the fourth exon of junctin while preserving the reading frame. Thus, three individual genes share common exons and open reading frames and use separate promoters to achieve differential expression, splicing, and function in a variety of tissues. This unusual form of exon sharing suggests that the functions of junctin, BAH, and humbug may be linked.
Characterization of Tropospheric Emission Spectrometer (TES) CO 2 for carbon cycle science

Abstract. We present carbon dioxide (CO2) estimates from the Tropospheric Emission Spectrometer (TES) on the EOS-Aura satellite launched in 2004. For observations between 40° S and 45° N, we find about 1 degree of freedom with peak sensitivity at 511 hPa. The estimated error is ~10 ppm for a single target and 1.3–2.3 ppm for monthly averages on spatial scales of 20°×30°. Monthly spatially-averaged TES data from 2005–2008 processed with a uniform initial guess and prior are compared to CONTRAIL aircraft data over the Pacific ocean, aircraft data at the Southern Great Plains (SGP) ARM site in the southern US, and the Mauna Loa and Samoa surface stations. Comparisons to Mauna Loa data show a correlation of 0.92, a standard deviation of 1.3 ppm, a predicted error of 1.2 ppm, and a ~2% low bias, which is subsequently corrected. Comparisons to SGP aircraft data over land show a correlation of 0.67 and a standard deviation of 2.3 ppm. TES data between 40° S and 45° N for 2006–2007 are compared to surface flask data, GLOBALVIEW, the Atmospheric Infrared Sounder (AIRS), and CarbonTracker. Comparison to GLOBALVIEW-CO2 ocean surface sites shows a correlation of 0.60 which drops when TES is offset in latitude, longitude, or time. At these same locations, TES shows a 0.62 and 0.67 correlation to CarbonTracker at the surface and 5 km, respectively. We also conducted an observing system simulation experiment to assess the potential utility of the TES data for inverse modeling of CO2 fluxes. We find that if biases in the data and model are well characterized, the averaged data have the potential to provide sufficient information to significantly reduce uncertainty on annual estimates of regional CO2 sources and sinks. Averaged pseudo-data at 10°×10° reduced uncertainty in flux estimates by as much as 70% for some tropical regions.
A Comparison of the Aldosterone‐blocking Agents Eplerenone and Spironolactone

Struthers et al,1 concludes that both eplerenone and spironolactone are effective and safe in the treatment of hypertension and heart failure, but there is no direct comparison of the 2 drugs. We showed, for the first time, that eplerenone is as effective as spironolactone in the management of patients with bilateral idiopathic hyperaldosteronism (IHA). 2 In a prospective, randomized, parallel-group, open-label, blinded-endpoint study, 34 patients with IHA were assigned to either eplerenone (50 up to 200 mg/daily) or spironolactone (50 up to 400 mg/daily) for 24 weeks. In the majority of patients (82.4% on eplerenone and 76.5% on spironolactone) blood pressure was normalized with monotherapy. Serum potassium levels were normalized in all patients at 4 weeks. There was no case of severe hyperkalemia, whereas mild hyperkalemia was observed in 5 patients, 2 in the spironolactone group and 3 in the eplerenone group. Subsequent dose decrease normalized the serum potassium levels after 1 week in all cases. Spironolactone has progesterone-like and antiandrogenic adverse effects due to nonspecific binding to steroid receptors and may cause painful gynecomastia, erectile dysfunction, and decreased libido in men and menstrual irregularity in women.1,3 In contrast, eplerenone has higher selectivity for the aldosterone receptor. In our study, 2 patients in the spironolactone group developed bilateral painful gynecomastia, which completely resolved after switching to eplerenone. In conclusion, the absence of severe adverse effects may improve compliance with eplerenone, but its use should be weighed against higher cost and the scarcity of data on its long-term effects in patients with IHA.
Genetic diversity and geographical distribution of wild Saccharomyces cerevisiae strains from the wine-producing area of Charentes, France

Electrophoretic karyotyping, mitochondrial DNA restriction fragment length polymorphism analysis, and PCR amplification of interspersed repeats were used to study the variability, phylogenetic affinities, and biogeographic distribution of wild Saccharomyces cerevisiae enological yeasts. The survey concentrated on 42 individual wine cellars in the Charentes area (Cognac region, France). A limited number (35) of predominant S. cerevisiae strains responsible for the fermentation process have been identified by the above molecular methods of differentiation. One strain (ACI) was found to be distributed over the entire area surveyed. There seemed to be little correlation between geographic location and genetic affinity.
Running for Your Life or Running for Your Dinner: What Drives Fiber‐Type Evolution in Lizard Locomotor Muscles?

Despite its role in whole‐animal performance, the adaptation of muscle physiology related to terrestrial locomotion remains underexplored. We tested evolutionary models based on predator escape and foraging strategies of lizards to assess whether fiber‐type composition of a leg muscle is adaptive for behavior. The best‐fitting model for fast‐twitch fiber‐type evolution was one based on predator‐escape strategy, while the foraging‐mode model fared poorly (Akaike Information Criterion with small sample size correction; \documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackage[OT2,OT1]{fontenc} \newcommand\cyr{ \renewcommand\rmdefault{wncyr} \renewcommand\sfdefault{wncyss} \renewcommand\encodingdefault{OT2} \normalfont \selectfont} \DeclareTextFontCommand{\textcyr}{\cyr} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} \landscape $$\Delta \mathrm{AICc}\,=29.7$$ \end{document} ). According to the predator‐escape model, lizards relying on sprints to avoid predators are predicted to have relatively higher proportions of fast glycolytic (FG) fibers (70%), while cryptic lizards are predicted to have relatively higher fast oxidative glycolytic (FOG) fiber proportions (77%). This pattern suggests an evolutionary trend toward greater FG (FOG) fiber composition among lizards that specialize in sprinting (crypsis). The best‐fitting model for slow‐twitch fibers had a single optimum, suggesting a common selective pressure across these lizards. The second‐best model explaining slow‐twitch fiber‐type evolution was Brownian motion ( \documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackage[OT2,OT1]{fontenc} \newcommand\cyr{ \renewcommand\rmdefault{wncyr} \renewcommand\sfdefault{wncyss} \renewcommand\encodingdefault{OT2} \normalfont \selectfont} \DeclareTextFontCommand{\textcyr}{\cyr} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} \landscape $$\Delta \mathrm{AICc}\,=0.80$$ \end{document} ), indicating some support for neutral evolution. We find evidence suggesting that different fiber types occurring in the same muscle can evolve under different evolutionary pressures.
Robust optimization of the inertially stabilized platforms

The features of the parametrical and structural robust optimization for systems of control by the initially stabilized platforms are considered. The main tasks of the initially stabilized platforms for the ground and marine vehicles are described. The statements of the parametrical and structural robust optimization problems for the initially stabilized platforms for the vehicles of the studied class are represented. The optimization results are given.
Anti-Tumor-Promoting Activity of Tibolone and its Metabolites

Abstract The aim of this study was to evaluate the cancer chemopreventive potential of the widely prescribed drug tibolone (17α-ethynyl-7α-methyl-5(10)-estren-3-one, CAS 5630-53-5) and its main metabolites, 17α-ethynyl-7α-methyl-4-estren-3-one (CAS 1162-60-3), 17α-ethynyl-7α-methyl-5(10)-estrene-3α,17β-diol (CAS 100239-44-9) and 17α-ethynyl-7α-methyl-5(10)-estrene-3β,17β-diol (CAS 100239-45-0), by studying their anti-tumor-promoting activity. To this aim the test compounds were submitted to the short term in vitro assay for the inhibition of Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) as a primary screening for anti-tumor promoters. All the compounds showed high inhibitory activity and low cytotoxicity as compared to literature data. To extend the study to an animal model, tibolone and its 3α-hydroxy metabolite (CAS 100239-44-9) were also assayed in the in vivo two-stage on mouse skin carcinogenesis test, exhibiting significant inhibitory effects on TPA promoted mouse skin papillomas formation. A comparison with literature data indicated them as more potent compounds than other steroids previously studied such as digitoxigenin, cortisone, hydrocortisone, and prednisolone.
List-colouring the square of an outerplanar graph

It is proved that if G is a K2,3-minor-free graph with maximum degree ∆, then ∆ + 1 6 χ(G) 6 ch(G) 6 ∆ + 2 if ∆ > 3, and ch(G) = χ(G) = ∆ + 1 if ∆ > 6. All inequalities here are sharp, even for outerplanar graphs.
The dynamics of measuring attachment

Shaver and Mikulincer’s review makes a strong case that self-reports of adult attachment are associated with attachment-related processes that are unconscious or at least that occur automatically and outside of awareness. Therefore, the common criticism that self-reports cannot meaningfully assess attachment orientations in a manner that is reective of dynamic processes is clearly false. The belief that interview measures are the only valid way to assess adult attachment is based in fundamental assumptions about what can and cannot be assessed in self-reports, and what needs to be assessed in determining adult attachment orientation. The AAI approach to assessing adult attachment is based on the assumption that assessment of defensive strategies, which operate at least partially outside of conscious awareness, is a necessary component in the evaluation of ‘states of mind’ with respect to attachment. Moreover, it is assumed that these strategies can be accurately scored (given appropriate training of coders) from the transcripts of interviews in which participants discuss the relationships they had with their parents in childhood. The attachment strategies identi ed in the AAI are assumed to re ect processes that operate outside the interview setting, especially in attachment-relevant contexts such as parenting. By denition, individuals with particular attachment strategies deny some types of psychological experiences and/or distort their responses to questions tapping these experiences. AAI advocates would therefore tend to conclude that it makes little sense to ask individuals with insecure attachment patterns direct questions about processes that are assumed to be defensively distorted and not open to conscious access. In contrast, they would argue that interview procedures are the most appropriate way to assess adult attachment because defensive strategies can be assessed and provide important clues to underlying attachment issues. Thus, it is common in the attachment literature to see comments such as: ‘Because we are interested in differences in processing attachment-related thoughts and feelings, we deal only with  ndings linking attachment states of mind [as assessed by the AAI] with psychopathology’ (Dozier, Stovall, & Albus, 1999, p. 498). How can self-reports be useful if this is true? One possibility is that self-reports about attachment are valid assessments of dynamic processes. This seems unlikely since these reports are not designed to assess such processes. Another possibility, suggested by Hesse (1999), is that states of mind with respect to early attachment experiences are not necessarily available to conscious awareness (therefore requiring interview measures to assess), but attachment orientations in the romantic domain are (therefore allowing for self-report assessments). However, we cannot think of any good reasons why the process of recalling and reporting on childhood experiences would be qualitatively different from the process of recalling and reporting on Attachment & Human Development Vol 4 No 2 September 2002 162–165