Miracle-dz/UniFAR-FTUs huggingface dataset:
Physiologic ischaemic training induces endothelial progenitor cell mobilization and myocardial angiogenesis via endothelial nitric oxide synthase related pathway in rabbits

Objective Ischaemia-induced angiogenesis promises to improve neovascularization by delivery of angiogenic factors or endothelial progenitor cells (EPCs) to cardiac ischaemic areas. In order to avoid the risk of excessive myocardial ischaemia, therefore, we hypothesized that physiological ischaemic training (PIT) of normal skeletal muscle might contribute to myocardial angiogenesis via nitric oxide mediated mobilization of EPCs from the bone marrow in the established rabbit model of controllable myocardial ischaemia. Methods The rabbits were grouped by sham-operation, myocardial ischaemia without PIT, PIT and PIT with pretreatment with the endothelial nitric oxide synthase (eNOS) inhibitor L-nitroarginine methyl ester (L-NAME). Controlled myocardial ischaemia was modelled by a water balloon constrictor implanted on the left ventricular branch in a rabbit. The PIT procedure included three cycles of 3 min of cuff inflation followed by 5 min of deflation on hind limbs of the rabbits for 4 weeks. At the endpoints, circulating EPCs (CD34+/Flk-1+) were measured by fluorescence-activated cell sorter; capillary density, by immunohistochemistry; blood flow, by a microsphere technique; endothelial nitric oxide synthase (eNOS) mRNA and protein, by real-time reverse transcriptase (RT)-PCR and Western blotting. Results The mRNA levels of eNOS were significantly higher in the PIT and L-NAME groups than in the sham-operation group (P < 0.05). Phospho-eNOS protein expression was higher in the PIT group than in the sham-operation and myocardial ischaemia without PIT groups (P < 0.05), and the effect was inhibited by L-NAME pretreatment (P < 0.05). Compared with sham-operation and myocardial ischaemia without PIT groups, the PIT group had the highest EPC count (P < 0.001), and the increase of capillary density (P < 0.01) and collateral blood flow (P < 0.05) in the ischaemic myocardium was consistent with the finding of EPC count. These effects were also inhibited by pretreatment with the eNOS inhibitor L-NAME. Capillary density and collateral blood flow were highly correlated with the increase of EPC count (r = 0.913 and r = 0.929, respectively, P = 0.000). Conclusion PIT improved EPC mobilization and contributed to compensatory neovascularization via eNOS-related pathway. These results might support the future development of strategies for therapeutic neovascularization.
Occlusive vs gauze dressings for local wound care in surgical patients: a randomized clinical trial.

OBJECTIVE To compare effectiveness and costs of gauze-based vs occlusive, moist-environment dressing principles. DESIGN Randomized clinical trial. SETTING Academic Medical Center, Amsterdam, the Netherlands. PATIENTS Two hundred eighty-five hospitalized surgical patients with open wounds. INTERVENTION Patients received occlusive (ie, foams, alginates, hydrogels, hydrocolloids, hydrofibers, or films) or gauze-based dressings until their wounds were completely healed. MAIN OUTCOME MEASURES Primary end points were complete wound healing, pain during dressing changes, and costs. Secondary end point was length of hospital stay. RESULTS Time to complete wound healing did not differ significantly between occlusive (median, 66 days; interquartile range [IQR], 29-133 days) and gauze-based dressing groups (median, 45 days; IQR, 26-106 days; log-rank P = .31). Postoperative wounds (62% of the wounds included) healed significantly (P = .02) quicker using gauze dressings (median, 45 days; IQR, 22-93 days vs median, 72 days; IQR, 36-132 days). Median pain scores were low and similar in the occlusive (0.90; IQR, 0.29-2.34) and the gauze (0.64; IQR, 0.22-1.95) groups (P = .32). Daily costs of occlusive materials were significantly higher (occlusive, euro6.34 [US $9.95] vs gauze, euro1.85 [US $2.90]; P < .001), but nursing time costs per day were significantly higher when gauze was used (occlusive, euro1.28 [US $2.01] vs gauze, euro2.41 [US $3.78]; P < .001). Total cost for local wound care per patient per day during hospitalization was euro7.48 (US $11.74) in the occlusive group and euro3.98 (US $6.25) in the gauze-based group (P = .002). CONCLUSIONS The occlusive, moist-environment dressing principle in the clinical surgical setting does not lead to quicker wound healing or less pain than gauze dressings. The lower costs of less frequent dressing changes do not balance the higher costs of occlusive materials. Trial Registration trialregister.nl Identifier: 56264738.
The arcade of Frohse and its relationship to posterior interosseous nerve paralysis.

1. The arcade of Frohse, a fibrous arch over the posterior interosseous nerve, may well play a part in causing progressive paralysis of the posterior interosseous nerve, both with and without injury. 2. Paralysis of the muscles supplied by this nerve with no evidence of recovery after six weeks, either electromyographic or clinical, should be treated by exploration and splitting of the arcade of Frohse.
Basic Residues in Azurocidin/HBP Contribute to Both Heparin Binding and Antimicrobial Activity*

Azurocidin/CAP37/HBP is an antimicrobial and chemotactic protein that is part of the innate defenses of human neutrophils. In addition, azurocidin is an inactive serine protease homolog with binding sites for diverse ligands including heparin and the bovine pancreatic trypsin inhibitor (BPTI). The structure of the protein reveals a highly cationic domain concentrated on one side of the molecule and responsible for its strong polarity. To investigate the role of this highly basic region, we produced three recombinant azurocidin mutant proteins that were altered in either one or both of two clusters of 4 basic residues located symmetrically on each side of a central cleft in the cationic domain. Two of the mutant proteins (Loop 3: R5Q, K6Q, R8Q, and R10Q; Loop 4: R61Q, R62Q, R63Q, and R65Q) exhibited little or no change in heparin and BPTI binding or in antimicrobial function. In contrast, the Loop 3/Loop 4 mutant (R5Q, K6Q, R8Q, R10Q, R61Q, R62Q, R63Q, and R65Q) in which all 8 basic residues were replaced showed greatly decreased ability to bind heparin and to kill Escherichia coli and Candida albicans. Thus, we report that the 8 basic residues that were altered in the Loop 3/Loop 4 mutant contribute to the ability of the wild-type azurocidin molecule to bind heparin and to kill E. coli and C. albicans. Because BPTI binding was comparable in wild-type and Loop 3/Loop 4 mutant protein, we conclude that the same 8 basic residues are not involved in the binding of BPTI to azurocidin, supporting the notion that the binding site for BPTI is distinct from the site involved in heparin binding and antimicrobial activity. Finally, we show that removal of all 4 positively charged amino acids in the 20–44 azurocidin sequence (DMC1: R23Q,H24S,H32S,R34Q), a region previously thought to contain an antimicrobial domain, does not affect the activity of the protein against E. coli, Streptococcus faecalis, andC. albicans.
Small molecule agents targeting the p53‐MDM2 pathway for cancer therapy

The powerful tumor suppressor p53 takes charge of a regulatory network to guard over the living cells from harmful effect of different forms of stress and eradicate the tumor cells for normal physiological condition maintenance. However the antitumor function of p53 is often attenuated or even omitted mainly due to two alternative mechanisms, direct gene alterations in p53 or negative controlled by MDM2 protein. In this article, overview on different therapeutic strategies that are exploited to restore the neoplasm therapeutic effect to p53 will be provided, including pharmacological rescue of mutant p53 and modulation of the p53‐MDM2 interaction. We attempt to focus on the medicinal chemistry aspects of small molecule agents targeting the p53‐MDM2 pathway and recent progress in these agents. In addition, the mechanism of action and anticancer activity of different classes of compounds targeting the p53‐MDM2 pathway, as well as structure–activity relationships, are discussed.
Tissue factor and Toll-like receptor (TLR)4 in hyperglycaemia-hyperinsulinaemia

Summary Diabetes mellitus (DM) patients have an increased incidence of cardiovascular events. Blood tissue factor-procoagulant activity (TF-PCA), the initiating mechanism for blood coagulation, is elevated in DM. We have shown that hyperglycaemia (HG), hyperinsulinaemia (HI) and combined HG+HI (induced using 24-hour infusion clamps) increases TF-PCA in healthy and type 2 DM (T2DM) subjects, but not in type 1 DM (T1DM) subjects. The mechanisms for this are unknown. DM patients have elevated plasma lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 ligand. We postulated that TLR4 plays a role in modulating TF levels. We studied the effect of HG+HI on TLR4 and TF-PCA in vivo during 24-hour HG+HI infusion clamps in healthy subjects, and T1DM and T2DM subjects, and in vitro in blood. In vivo, in healthy subjects, 24-hour HG + HI infusion increased TLR4 six-fold, which correlated with TF-PCA (r=0.91, p<0.0001). T2DM patients showed smaller increases in both. In T1DM subjects, TLR4 declined (50%, p<0.05) and correlated with TF-PCA (r=0.55; p<0.05). In vitro, HG (200 mg/dl added glucose) and HI (1-100 nM added insulin) increased TF-PCA in healthy subjects (˜2-fold, 2-4 hours). Insulin inhibited by ~30% LPSinduced increase in TF-PCA and high glucose reversed it. TLR4 levels paralleled TF-PCA (r=0.71, p<0.0001); HG and HI increased TLR4 and insulin inhibited LPS-induced TLR4 increase. This is first evidence that even in healthy subjects, HG of short duration increases TLR4 and TFPCA, key players in inflammation and thrombosis. TLR4-TF interplay is strikingly different in non-diabetic, T1DM and T2DM subjects.
Suramin analogs inhibit human angiogenesis in vitro.

BACKGROUND Suramin is a polysulfonated naphthylurea that inhibits tumor cell proliferation and angiogenesis, but the widespread use of this drug has been limited by significant neurologic toxicity. A series of suramin analogs that may exhibit less toxicity in vivo have been synthesized. We hypothesized that these novel analogs would have antiangiogenic properties equal to or greater than those of suramin when evaluated in an in vitro human placental vein angiogenesis model. METHODS Human placental veins (n = 72 per group) were cultured in a 0.3% fibrin clot for a period of 14 days. Three suramin analogs (NF 145, NF 248, NF 293) and suramin were tested at 56 and 560 microM concentrations to determine their effect on the development of an angiogenic response. Experiments were repeated for each analog on veins from three different placentas. The percentage of wells that initiated an angiogenic response was calculated and compared with initiation in a control group (n = 141). RESULTS The three suramin analogs inhibited angiogenesis in a dose-dependent fashion, with all compounds exhibiting near-complete inhibition of angiogenesis at 560 microM. The effects of these analogs were equal to or greater than those of suramin. CONCLUSION Suramin analogs with structural alterations inhibit human angiogenesis at concentrations equivalent to those seen in vivo. These analogs may be more effective antiangiogenic agents than suramin and may have less potential for toxicity.
Safety evaluation of naringenin upon experimental exposure on rat gastrointestinal epithelium for novel optimal drug delivery

Abstract Objective: To assess the effect of naringenin on the intestinal biochemical composition, function and histology for gastrointestinal toxicity since it has not yet been adequately exploited for safety through standard assays. Methods: Here, we describe naringenin (1 mM, 10 mM and 100 mM, respectively) or sodium deoxycholate (10 mM) effects on isolated brush border membrane from intestinal segments with single pass intestinal perfusion using lactate dehydrogenase, alkaline phosphatase and protein assays. MTT assay was used for cytotoxicity studies. Everted gut sac studies were used for evaluating the transport of nutrients across the intestinal segments. Lucifer yellow was used for paracellular permeability, followed by histological changes and surface characteristic studies of intestinal sacs. Results: The results indicated no significant alterations with naringenin, although significant (p < 0.01) changes were noticed with sodium deoxycholate in the activity of the rat intestinal brush border associated enzymes such as LDH, followed by intact cell viability with marked decrease in the villi height of the intestinal segments. Conclusions: These observations indicate that naringenin was harmless upon exposure to rat gastrointestinal epithelium, clearly demonstrating the potential use of naturally occurring bioflavonoid as safe and novel pharmaceutical adjuvant in oral dosage forms as P-gp inhibitor.
Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages

Macrophages acquire strikingly different properties that enable them to play key roles during the initiation, propagation, and resolution of inflammation. Classically activated (M1) macrophages produce proinflammatory mediators to combat invading pathogens and respond to tissue damage in the host, whereas regulatory macrophages (M2b) produce high levels of anti-inflammatory molecules, such as IL-10, and low levels of proinflammatory cytokines, like IL-12, and are important for the resolution of inflammatory responses. A central problem in this area is to understand how the formation of regulatory macrophages can be promoted at sites of inflammation to prevent and/or alleviate chronic inflammatory and autoimmune diseases. Here, we demonstrate that the salt-inducible kinases (SIKs) restrict the formation of regulatory macrophages and that their inhibition induces striking increases in many of the characteristic markers of regulatory macrophages, greatly stimulating the production of IL-10 and other anti-inflammatory molecules. We show that SIK inhibitors elevate IL-10 production by inducing the dephosphorylation of cAMP response element-binding protein (CREB)-regulated transcriptional coactivator (CRTC) 3, its dissociation from 14-3-3 proteins and its translocation to the nucleus where it enhances a gene transcription program controlled by CREB. Importantly, the effects of SIK inhibitors on IL-10 production are lost in macrophages that express a drug-resistant mutant of SIK2. These findings identify SIKs as a key molecular switch whose inhibition reprograms macrophages to an anti-inflammatory phenotype. The remarkable effects of SIK inhibitors on macrophage function suggest that drugs that target these protein kinases may have therapeutic potential for the treatment of inflammatory and autoimmune diseases.
ROOT HAIR DEFECTIVE 4 Encodes a Phosphatidylinositol-4-Phosphate Phosphatase Required for Proper Root Hair Development in Arabidopsis thaliana

Julie M. Thole,a Joop E.M. Vermeer,b Yanling Zhang,c Theodorus W.J. Gadella Jr.,d and Erik Nielsena,c,1 a Department of Biology, Washington University, St. Louis, Missouri 63130 b Section of Plant Physiology, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 SM Amsterdam, The Netherlands c Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109 d Section of Molecular Cytology, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 SM Amsterdam, The Netherlands
Severe complications associated with varicella: Province of Quebec, April 1994 to March 1996.

OBJECTIVE To determine the frequency and severity of serious complications associated with varicella in Quebec; the frequency and severity of cases of congenital varicella; and hospital costs associated with hospitalizations for varicella. STUDY DESIGN All hospitalizations related to varicella were identified through the use of a hospital data bank and pertinent data were collected from hospital records. SETTING Province of Quebec with a population of 6,895,960 people. STUDY POPULATION All cases with a principal or secondary diagnosis of varicella hospitalized in Quebec between April 1, 1994 and March 31, 1996. OUTCOME MEASURES Types of complications and reason for hospitalization, risk of complications and calculation of associated costs were studied. RESULTS Nine hundred nine eligible hospitalizations were identified between April 1, 1994 and March 31, 1996. In all, 583 (64.1%) hospitalizations were for the treatment of complications, 127 (14.0%) for administration of intravenous acyclovir and 199 (21.9%) for supportive care. Healthy people accounted for 644 (70.8%) hospitalizations and immunosuppressed individuals for 136 (15.0%). Among children, one-half of the principal complications were skin infections, while 13.5% and 8.4% of principal complications were pneumonia and neurological complications, respectively. Among adults, the most common complication was pneumonia, with a rate of 43.5%, followed by thrombocytopenia and skin infections, with rates of 22.2% and 14.8%, respectively. The complication rate was 29.2 cases/10,000 cases of varicella. CONCLUSIONS Although perceived as a benign childhood disease by the general population, varicella may be accompanied by severe complications. Morbidity associated with varicella is one of the elements that must be considered when evaluating the usefulness of varicella vaccine.
Mackey Dynamic Hematological Disease : A Review

We review the basic characteristics of four periodic hematological disorders (periodic auto-immune hemolytic anemia, cyclical thrombocytopenia, cyclical neutropenia and periodic chronic myelogenous leukemia) and examine the role that mathematical modeling and numerical simulations have played in our understanding of the origin of these diseases and in the regulation of hematopoiesis.
Self-Determination Theory and Computer-Mediated Support: Modeling Effects on Breast Cancer Patient’s Quality-of-Life

ABSTRACT A breast cancer diagnosis typically results in dramatic and negative effects on an individual’s quality of life. Web-based interactive support systems such as the Comprehensive Health Enhancement Support System (CHESS) offer one avenue for mitigating these negative effects. While evidence supports the efficacy of such systems, evaluations typically fail to provide a true test of the theorized model of effects, treating self-determination theory’s constructs of competence, relatedness, and autonomy as outcomes rather than mediators. Using path analysis, this study tests the nature of the proposed mediated relationship between system engagement and quality-of-life indicators utilizing data collected from women (N = 90) who participated in the treatment condition of a CHESS randomized controlled trial. Findings support a latent model, indicating that system effects are mediated through an intertwined measure of autonomy, competence, and relatedness.
LINE‐ 1 hypomethylation level as a potential prognostic factor for epithelial ovarian cancer

A genome-wide hypomethylation is a common and crucial event in cancer. This study was to evaluate common epithelial ovarian cancer (EOC) if long interspersed element-1 (LINE-1) repetitive sequences methylation levels are progressively decreased during multistage carcinogenesis and there are the correlation between LINE-1 methylation levels and clinicopathologic characteristics. A total of 59 pairs of microdissected EOC tissues obtained from patients with EOC were examined for the methylation levels of LINE-1 repetitive sequences by a COBRALINE-1 (combined bisulfite restriction analysis of LINE-1) PCR protocol. The methylation levels were correlated with clinicopathologic parameters to determine the potential role of global hypomethylation as a prognostic marker for EOC. The LINE-1 methylation levels of 59 EOCs, 34.87 ± 7.39%, were lower than in representative normal ovarian tissues (46.89 ± 8.31%; 95% CI: 9.42–14.62; P< 0.001, paired-two-tailed t test). A decrease in the LINE-1 level of methylation was correlated with histological subtypes, higher FIGO and advanced tumor grade. Patients with greater hypomethylation (i.e., a methylation level ≤ 34.87%) had poorer mean overall survival (P= 0.003) and a lower mean progression-free interval (P< 0.001). Therefore, progressive decrease in LINE-1 methylation level is a common and important epigenetic process in ovarian multistep carcinogenesis. Moreover, the COBRALINE-1 method has the potential to be used as a tumor marker for EOC.
Some acoustic characteristics in the voices of 6- to 10-year-old children and adults: a comparative sex and developmental perspective

This study is a follow-up investigation of some of the acoustic characteristics reported for a group of twenty 6-, 8- and 10-year-old children's voices (Whiteside SP, Hodgson C. Log Phon Vocol 1999; 24: 6-13) and compares the data of these children with data from a group of nine adults. The acoustic characteristics for both the children and the adults were examined as a function of age and sex. Fundamental frequency (F0) and the standard deviation (SD) of F0 were investigated for the entire duration of a phrase-final vowel. In addition, the first three formant frequencies of the midpoints for the phrase-final vowel were also investigated, with reference to phonetic context. All acoustic parameters were investigated by examining the age, sex and context-determined differences. Results indicated significant age differences for all acoustic parameters investigated, which were characterized by a general decrease in the frequency values of parameters with increasing age. In addition, significant sex differences were found for all parameters, with the females generally having higher formant frequency values than their male peers across all ages. Significant phonetic context differences were only found for the second formant frequency, with formant values being highest for the context ? jar? and lowest for the context ? bar? No significant interactions were found for age-by-context, sex-by-context or age-by-sex-context comparisons. Relative formant frequency differences were also examined using Fant's Kn factor, by considering sex-, age- and context-linked patterns. The data also provided some evidence for parallel developmental patterns in the different phonetic contexts of a phrase-final vowel. Furthermore, the results showed that there was some evidence of all three types of the aforementioned patterns in addition to phonetic context-determined changes in K2 factor values. The results reported here, therefore, provide further evidence for age- and sex-linked differences in the patterns of development and maturation of the vocal apparatus.
Diabetic Patient Compliance as a Function of Patient Counseling

The impact of a specially designed patient education program upon the diabetes-related knowledge and compliance of insulin dependent diabetic patients was investigated. The program consisted of an audiovisual presentation, illustrated handout material, and pharmacist-patient counseling. Based on statistical considerations, 65 eligible patients were assigned systematically to a control group (Group I) and a study group (Group II) and were evaluated for compliance following a standardized protocol. Immediately following the interview, Group II patients were instructed utilizing the patient education program. Scores for initial and final evaluations of knowledge and compliance were compared using appropriate statistical procedures. The program was successful in producing improvements in both knowledge and compliance but a need for individualization of patient education efforts was indicated. Significant improvements in compliance were not observed among patients older than the mean age for study patients and those with diabetes complicated by cardiovascular and hypertensive disease.