Biocompounds Attenuating the Development of Obesity and Insulin Resistance Produced by a High-fat Sucrose Diet.
The use of biocompounds as agents with potential anti-obesity effects might be a feasible alternative to the prescription of traditional drugs in the near future. The goal of the present study was to screen five different compounds in relation to their ability to prevent body weight gain and ameliorate obesity-associated metabolic impairments, namely insulin resistance. For this purpose, seventy Wistar rats were randomly assigned into seven experimental groups. A standard diet-fed control group (control, n=10); a high-fat, high-sucrose diet-fed group (HFS, n=10) and five experimental groups which were fed the HFS diet supplemented with one of the following biocompounds; curcumin (100 mg/kg bw, n=10), chlorogenic acid (50 mg/kg bw, n=10), coumaric acid (100 mg/kg bw, n=10), naringin (100 mg/kg bw, n=10) and leucine (1% of diet, n=10). These results confirm the effectiveness of all the compounds to reduce significantly food efficiency, despite the significant higher food intake. Moreover, visceral fat mass percentage was significantly decreased after naringin and coumaric acid supplementation. In fact, this finding might be related to the considerable amelioration of HOMA-IR index detected in naringin-treated animals. A significant reduction in serum insulin levels and an improvement in the intraperitoneal glucose tolerance test and AUC were found in leucine- and coumaric acid-treated rats, respectively. In summary, the tested biocompounds, particularly naringin, coumaric acid and leucine, showed potential benefits in the prevention of obesity-related complications in rats, at least at the proved doses.


The spectrum of beta-thalassemia mutations in the Oran region of Algeria.
In order to delineate the spectrum of beta-globin gene defects causing beta-thalassemia in the Oran region of Algeria, we have analyzed a representative sample of 31 beta-thalassemia patients. This led to the detection of 10 mutations. Four of them [nonsense codon 39 (C->T), IVS-I-110 (G->A), IVS-I-2 (T->C), and frameshift codon 6 (-A)] account for approximately 77% of the beta-thalassemia chromosomes. Three of these mutants are also widespread in Mediterranean populations, whereas the fourth, IVS-I-2 (T->C), appears typical of the Oranese population. The six other variants are less frequent. The possible origin of these mutated alleles, either by recurrent mutational event or by migration from other populations, is discussed.


Propolis supplementation in obese patients with non-alcoholic fatty liver disease: effects on glucose homeostasis, lipid profile, liver function, anthropometric indices and meta-inflammation.
This study assessed the effects of propolis supplementation on glucose homeostasis, lipid profile, liver function, anthropometric indices and meta-inflammation in patients with non-alcoholic fatty liver disease (NAFLD). In this double-blind placebo-controlled randomized clinical trial, 44 patients with NAFLD confirmed by ultrasonography findings were randomly allocated into either the "propolis" (n = 23) or "placebo" (n = 21) group along with a calorie-restricted diet (-500 kcal d-1) for 8 weeks. Fasting serum levels of metabolic factors, liver enzymes, and inflammatory factors, as well as anthropometric indices, dietary intake and appetite status were assessed pre-and post-intervention. The liver fibrosis score, homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were also calculated. The weight, body mass index (BMI), waist and hip circumferences, and waist to height ratio significantly decreased in both groups (p < 0.001), while the waist to hip ratio (p = 0.006) and serum level of total cholesterol (p = 0.038) decreased only in the propolis arm. However, no significant changes in anthropometric measurements and lipid profile were found between the groups at the end of the intervention. Fasting blood sugar (p = 0.037), the serum insulin level (p = 0.040), HOMA-IR (p = 007), desire to eat sweet foods (p = 0.005) and the NAFLD fibrosis score (p = 0.013) decreased significantly in the propolis group compared to the placebo group, post-intervention after adjusting for baseline values and potential confounders. However, QUICKI showed a significant increase (p = 0.015) in the propolis arm compared to the placebo at the study endpoint. Although there were significant reductions in the serum levels of inflammatory factors including tumor necrosis factor-α (TNF-α), toll-like receptor-4 (TLR-4) and monocyte chemoattractant protein-1 (MCP-1), as well as liver enzymes and severity of fatty liver, between-group differences were not statistically significant after adjusting for the potential confounding factors. The estimated number needed to treat (NNT) due to 8-week propolis supplementation (510 mg per day) for at least 1-point improvement in NAFLD severity was found to be approximately 3. In conclusion, propolis supplementation along with a calorie-restricted diet for 8 weeks could significantly improve the glucose homeostasis, hepatic fibrosis score and liver function in patients with NAFLD. Further clinical trials are encouraged to study the effects of propolis supplementation in patients with long-term NAFLD.


Fecal microbial transplantation limits neural injury severity and functional deficits in a pediatric piglet traumatic brain injury model.
Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. Due to bidirectional communication between the brain and gut microbial population, introduction of key gut bacteria may mitigate critical TBI-induced secondary injury cascades, thus lessening neural damage and improving functional outcomes. The objective of this study was to determine the efficacy of a daily fecal microbial transplant (FMT) to alleviate neural injury severity, prevent gut dysbiosis, and improve functional recovery post TBI in a translational pediatric piglet model. Male piglets at 4-weeks of age were randomly assigned to Sham + saline, TBI + saline, or TBI + FMT treatment groups. A moderate/severe TBI was induced by controlled cortical impact and Sham pigs underwent craniectomy surgery only. FMT or saline were administered by oral gavage daily for 7 days. MRI was performed 1 day (1D) and 7 days (7D) post TBI. Fecal and cecal samples were collected for 16S rRNA gene sequencing. Ipsilateral brain and ileum tissue samples were collected for histological assessment. Gait and behavior testing were conducted at multiple timepoints. MRI showed that FMT treated animals demonstrated decreased lesion volume and hemorrhage volume at 7D post TBI as compared to 1D post TBI. Histological analysis revealed improved neuron and oligodendrocyte survival and restored ileum tissue morphology at 7D post TBI in FMT treated animals. Microbiome analysis indicated decreased dysbiosis in FMT treated animals with an increase in multiple probiotic Lactobacilli species, associated with anti-inflammatory therapeutic effects, in the cecum of the FMT treated animals, while non-treated TBI animals showed an increase in pathogenic bacteria, associated with inflammation and disease such in feces. FMT mediated enhanced cellular and tissue recovery resulted in improved motor function including stride and step length and voluntary motor activity in FMT treated animals. Here we report for the first time in a highly translatable pediatric piglet TBI model, the potential of FMT treatment to significantly limit cellular and tissue damage leading to improved functional outcomes following a TBI.


Increased multi-drug resistance among the elderly on admission to the hospital--a 12-year surveillance study.
Resistance to antimicrobials continues to increase worldwide. Data suggest that older patients are among the main reservoirs of multidrug-resistant organisms (MDROs) in the hospital. We hypothesized that older patients (≥ 65 years of age) are more likely to harbor MDRO at hospital admission. We compared rates of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and multidrug-resistant gram-negative bacteria (MDRGN) recovered from clinical cultures within the first 48 h of admission to an adult acute care hospital between the elderly (≥ 65 years old) and young per 1000 age-stratified admissions over a 12-year study period. Trends in antimicrobial resistance, sites of recovery and species for MDRGN were also characterized. An average of 7534 positive bacterial cultures were collected per year. The admission prevalence per 1000 age-stratified admissions was consistently higher among the elderly for all three MDRO under investigation. Among the elderly, the admission prevalence increased significantly for VRE (0.89 in 1998 to 3.62 in 2009 per 1000 admissions; p < 0.001) and MDRGN (1.41 in 1998 to 11.33 in 2009 per 1000 admissions; p < 0.001). Percentage resistant for all three MDRO increased as well. These data suggest that elderly patients are contributing substantially to the influx of MDRO into the hospital setting.


Respiratory load compensation in awake and sleeping dogs.
We have investigated immediate and progressive ventilatory responses to external elastic loads in five dogs with cervical vagal loops. Three dogs were studied while awake (W) and during non-REM sleep (S); the other two during barbiturate anesthesia (A). Elastic loads were applied at the end expiration for 1-6 breaths by having the dogs breathe from a rigid container (partial load) or against an occluded airway (infinite load). "Effective" elastance (EE) was determined from the tidal volume (VT)-tracheal pressure relationships of the unloaded, partially loaded, and infinitely loaded breaths. Passive thoracic elastance during W and S averaged 16.7 cmH2O/1. EE averaged 55.8 cmH2O/1 during W, 54.7 during S, and 59.5 during A. Vagal blockade (VB) induced large changes in VT but no change in EE in W or S; during A, EE decreased 37.5%. With sustained loading (partial) there was a progressive increase in VT but a corresponding increase in chemical (primarily hypoxic) respiratory drive, so that EE remained constant during five loaded breaths. VB augmented the progressive increase in VT during W or S but virtually abolished the increase in A. Thus the responses to elastic loads in W and S are similar and independent of conscious reactions or vagal influence; responses during A differ considerably. "Progressive load compensation" is a reflection of increasing of increasing chemical drive and not of progressive changes in EE.


Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations.
The widespread introduction of artemisinin-based combination therapy has contributed to recent reductions in malaria mortality. Combination therapies have a range of advantages, including synergism, toxicity reduction, and delaying the onset of resistance acquisition. Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of effective drugs with distinct target pathways. To fast-track antimalarial drug discovery, we have previously employed drug-repositioning to identify the anti-amoebic drug, emetine dihydrochloride hydrate, as a potential candidate for repositioned use against malaria. Despite its 1000-fold increase in in vitro antimalarial potency (ED50 47 nM) compared with its anti-amoebic potency (ED50 26-32 uM), practical use of the compound has been limited by dose-dependent toxicity (emesis and cardiotoxicity). Identification of a synergistic partner drug would present an opportunity for dose-reduction, thus increasing the therapeutic window. The lack of reliable and standardised methodology to enable the in vitro definition of synergistic potential for antimalarials is a major drawback. Here we use isobologram and combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define drug interactivity in an objective, automated manner. The method, based on the median effect principle proposed by Chou and Talalay, was initially validated for antimalarial application using the known synergistic combination (atovaquone-proguanil). The combination was used to further understand the relationship between SYBR Green viability and cytocidal versus cytostatic effects of drugs at higher levels of inhibition. We report here the use of the optimised Chou Talalay method to define synergistic antimalarial drug interactivity between emetine dihydrochloride hydrate and atovaquone. The novel findings present a potential route to harness the nanomolar antimalarial efficacy of this affordable natural product.


Analysis of interaction of spinal and supraspinal reflex pathways involved in physiological tremor.
A model of feedback type in which physiological tremor are produced by both muscular skeletal system and reflex action is described. Analysis of this model shows that the interaction between the spinal and the supraspinal reflex pathways is important in responsible for low and high frequency oscillations of physiological tremor. Particularly the effect of gain ratio of the two pathways is studied in order to examine the role for the two reflex pathways in controlling neuromuscular oscillations. The existence of a critical point of the gain ratio at which one oscillating frequency transitions to two ones is predicted theoretically. A shift of the critical point with variations of weight load is found and suggests a changeable correlation relation between the spinal and the supraspinal pathways due to loading conditions. Our computations for physiological tremor demonstrate the results that the high frequency component of about 25 Hz is produced by the muscle-spinal reflex loop, and the low frequency component of about 10 Hz originates from the central nervous system or from supraspinal reflex loop. Several relations derived in this study are described, and they can be compared with experimental observations. Our model sheds considerable light on the details of the possible mechanism for physiological tremor. In addition, a possibility arising from our study is that the tremulous oscillation associated with some pathological states, say Parkinson's disease, may arise from modified gains in one or more of the reflex pathways.


CT-invariant quantum spin Hall effect in ferromagnetic graphene.
We predict a quantum spin Hall effect (QSHE) in ferromagnetic graphene under a magnetic field. Unlike the previous QSHE, this QSHE appears in the absence of spin-orbit interaction and thus, is arrived at from a different physical origin. The previous QSHE is protected by the time-reversal (T) invariance. This new QSHE is protected by CT invariance, where C is the charge conjugation operation. Because of this QSHE, the longitudinal resistance exhibits quantum plateaus. The plateau values are at 1/2, 1/6, 3/28, ..., (in units of h/e2), depending on the filling factors of the spin-up and spin-down carriers. The spin Hall resistance is also investigated and is found to be robust against the disorder.


A multiplicity of targets: evaluating composite endpoint studies of the GLP-1 receptor agonists in type 2 diabetes.
Current type 2 diabetes (T2D) treatment guidelines include weight maintenance or loss, avoidance of hypoglycemia, and targets for blood pressure and circulating lipids, in addition to glycemic control. Increasingly, clinical trials and meta-analyses employ composite endpoints to capture the net clinical benefit of a given T2D intervention. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) represent a new class of injected antihyperglycemic agents that may be well suited to reaching many of these targets among patients failing on metformin monotherapy. Using MEDLINE, Embase and Google Scholar, studies were sought that employed composite endpoints and that reported outcomes with exenatide and/or liraglutide. Bibliographies of relevant review articles were consulted to search for additional reports. Many trials have used the combination of HbA1c <7%, no weight gain and no hypoglycemic episodes as the composite endpoint in evaluating T2D therapies; however, at least 15 other distinct composite endpoints have been reported. Findings were relatively consistent across studies, regardless of how the composite endpoint was defined. Specifically, the GLP-1 RAs appear to be superior to other agents in their efficacy in providing T2D patients failing on metformin with a net clinical benefit, which can include avoidance of hyperglycemia and maintenance or improvement in body weight. Use of composite endpoints represents an important advance in T2D. While no single such endpoint has achieved dominance in the field, widely used composite endpoints capture efficacy in glycemic control as well as safety and effects on markers of cardiovascular risk.


SUNCT syndrome. A clinical review.
The clinical features of SUNCT syndrome have been reviewed in 21 patients. There were 17 men and 4 women, rendering a clear male preponderance (ratio of 4.25). The mean age at onset was around 51 years. Attacks were experienced mostly in the orbital/periorbital area and always recurred on the same side, with an erratic temporal pattern and remissions of varying lengths. Most attacks were moderate to severe in intensity and burning, electrical, or stabbing in character. The attacks were regularly accompanied by prominent, ipsilateral, conjunctival injection; tearing; and rhinorrhea or nasal obstruction. There were many precipitating mechanisms. Exclusively spontaneous attacks were described in 3 patients. The usual duration of paroxysms ranged from 10 to 60 seconds, Whereas the longest duration varied from 60 to 300 seconds. The frequency of attacks during the symptomatic periods varied from less than 1 attack daily to more than 30 per hour. In the majority of patients, supplementary examinations failed to show any notable abnormality. However, 2 patients were documented to have a symptomatic form of SUNCT, with a vascular malformation in the ipsilateral cerebellopontine angle. A variety of drugs and local anesthetic blockades, inclusive of tic douloureux drugs, were tried, but a persistent, convincingly beneficial effect was generally lacking. SUNCT syndrome is in the differential diagnosis when encountering unilateral, orbital/periorbital headache syndromes.


Long-Term Results of 0.19mg Fluocinolone Acetonide Insert for Treatment of Non-Infectious Uveitis in Clinical Practice.
To evaluate the long-term outcomes of patients with non-infectious uveitis treated with 0.19 mg fluocinolone acetonide insert (FAi) for up to 36 months in clinical practice. A retrospective study conducted at a single uveitis center. Fifty eyes of 39 patients were included. Mean best corrected visual acuity (BCVA) and central retinal thickness (CRT) remained stable until month 36 after FAi implantation (61.04 vs. 70.25 letters and 370.8 vs. 332.5 µm, respectively). The recurrence rate was 34% (17 eyes) after 36 months, of which 82% (14 eyes) received high-dose corticosteroids before FAi. Mean intraocular pressure (IOP) remained unchanged (13.38 vs. 15.74 mmHg), while most phakic eyes (13 of 14 eyes) required cataract surgery. We show that FAi effectively prevents recurrences of non-infectious uveitis for up to three years in clinical practice, comparable with randomized clinical trials. Patients who received high-dose corticosteroids before FAi have an increased risk for early recurrence and should be considered for scheduled re-treatment.


A fatal case of infantile malignant osteopetrosis complicated by pulmonary arterial hypertension after hematopoietic stem cell transplantation.
Infantile malignant osteopetrosis (IMO) is a rare and fatal autosomal recessive condition characterized by a generalized increased in bone density. Hematopoietic stem cell transplantation (HSCT) is the only effective and rational therapy with achieving long-term disease-free survival. However, complications with HSCT for IMO remain unclear. Here we describe a male infant with IMO, carrying two novel mutations in the T-cell immune regulator 1 (TCIRG1) gene. The TCIRG1 gene encodes the a3 subunit of vacuolar H(+)-ATPase that plays an essential role in the resorptive function of osteoclasts. Direct sequencing of all 20 exons of the TCIRG1 gene revealed a single nucleotide change in exon 11 (c1305 G > T), which causes the substitution of Asp (GAT) for Glu (GAG) at position 435, and a two-nucleotide deletion in exon 16 (c1952-1953 del CA), causing a frame-shift mutation. However, the functional consequence of each mutation remains to be determined. Allogeneic HSCT was performed in the patient at the age of nine months. Donor engraftment was achieved, and abnormal bone metabolism and extramedullary hematopoiesis were corrected. Graft-versus-host disease was mild (grade I). However, the patient died of complication of pulmonary arterial hypertension at seven months after the HSCT. Postmortem examination revealed prominent vascular wall thickening of the pulmonary artery and macrophage infiltration to alveoli. It should be noted that a patient with IMO has a risk for pulmonary arterial hypertension, and the evaluation of pulmonary arterial flow should be included in the assessment of each patient with IMO even after HSCT.


Distinct E2F-mediated transcriptional program regulates p14ARF gene expression.
The tumor suppressor p14(ARF) gene is induced by ectopically expressed E2F, a positive regulator of the cell cycle. The gene is expressed at low levels in normally growing cells in contrast to high levels in varieties of tumors. How p14(ARF) gene is regulated by E2F in normally growing cells and tumor cells remains obscure. Here we show that regulation of p14(ARF) gene by E2F is distinct from that of classical E2F targets. It is directly mediated by E2F through a novel E2F-responsive element that varies from the typical E2F site. The element responds to E2F activity resulting from ectopic E2F1 expression, inactivation of pRb by adenovirus E1a or shRNA, but not to phosphorylation of pRb by serum stimulation or ectopic cyclin D1/cyclin-dependent kinase-4 expression in normal human fibroblasts. The element has activity in various tumor cells with defective pRb, but not in normally growing cells. These results indicate that the distinct regulation constitutes the basis of p14(ARF) function as a tumor suppressor, discriminating abnormal growth signals caused by defects in pRb function from normal growth signals.


Myogenin expression is necessary for commitment to differentiation and is closely related to src tyrosine kinase activity in quail myoblasts transformed with Rous sarcoma virus.
Quail myoblasts transformed with a temperature-sensitive mutant of Rous sarcoma virus (QM-RSV cells) proliferate at 35.5 degrees C, a permissive temperature for RSV, but differentiate at 41 degrees C, a nonpermissive temperature, with the formation of multinucleated myotubes and the synthesis of muscle-specific proteins. Tyrosine kinase activity of the src gene product derived from RSV is closely related to regulation of this temperature-dependent differentiation, and the cells obtain commitment to differentiation by incubation for about 12 h at 41 degrees C with dephosphorylation of tyrosine-phosphorylated protein(s). It was examined how myogenin, a member of myogenic regulatory factors, participates in commitment to differentiation and tyrosine dephosphorylation of QM-RSV cells. Myogenin was expressed within 8 h and reached a plateau within 10 h at 41 degrees C. Each cell clone whose differentiation proceeded faster or slower than the parental QM-RSV cells was reflected by a faster or slower myogenin expression, corresponding to the time that is required for commitment to differentiation. It was suggested that there is a lag time between myogenin expression and the acquisition of commitment in QM-RSV cells. On the other hand, at 35.5 degrees C, a condition which suppresses differentiation, myogenin expression was not detected. However, herbimycin A, an inhibitor of protein tyrosine kinase, induced myogenin expression even at 35.5 degrees C. On the contrary, myogenin expression was inhibited at 41 degrees C by sodium orthovanadate, an inhibitor of tyrosine-phosphorylated protein phosphatase. Furthermore, forced induction of myogenin into the cells cultured at 35.5 degrees C resulted in the formation of multinucleated myotubes and the synthesis of muscle-specific proteins. These results suggest that myogenin expression is one of the indispensable conditions for the acquisition of commitment to differentiation and is regulated by tyrosine phosphorylation and dephosphorylation of some protein(s) in QM-RSV cells.


Tributylhexadecylphosphonium bromide, a novel nuclear factor of activated T cells signaling inhibitor, blocks interleukin-2 induction associated with inhibition of p70 ribosomal protein S6 kinase phosphorylation.
Transcriptional factors of the nuclear factor of activated T cells (NFAT) family are involved in T cell signaling. Many NFAT signaling inhibitors, such as cyclosporin A (CsA) and tacrolimus, abrogate dephosphorylation of NFAT proteins by inhibiting calcineurin activity. In pursuit of a novel type of NFAT signaling inhibitor, we screened our chemical library using the NFAT-dependent reporter assay and identified tributylhexadecylphosphonium bromide (THPB) as a selective NFAT signaling inhibitor. THPB inhibited NFAT-dependent reporter activity, and the induction of interleukin-2 (IL-2) at both mRNA and protein levels by calcium stimulation. Moreover, THPB had an additive effect on the inhibition of IL-2 induction with CsA. Unlike CsA, THPB did not affect dephosphorylation of NFAT1, but suppressed phosphorylation of p70 ribosomal protein S6 kinase (p70S6K). These results suggest that THPB may be a novel type of NFAT signaling inhibitor that acts in association with inhibition of p70S6K phosphorylation.


Inhibition of estrogen-induced kidney carcinogenesis in Syrian hamsters by modulators of estrogen metabolism.
Quinone metabolites of catechol estrogens have been postulated to mediate estradiol-induced carcinogenesis. In this study, this postulate was examined by investigating the effect of modulators of quinone metabolism on estradiol-induced tumor incidence in male Syrian hamsters. 2(3)-t-Butyl-4-hydroxyanisol (BHA) and dicumarol which are known to stimulate or inhibit respectively, the activity of quinone reductase, lowered tumor incidence by 33 and 42% respectively (3/9 and 5/12 tumor-free animals/total respectively), from 100% (13/13) observed with 17 beta-estradiol (E2) treatment only. Ebselen, a substance with glutathione peroxidase-like activity, and sodium 2-mercaptoethanesulfonate (Mesna), a cytoprotective thiol-containing agent, were only marginally effective in decreasing the estradiol-induced kidney tumor incidence (3/11 and 4/19 tumor-free animals/total respectively). The lowering of tumor incidence by BHA and dicumarol correlated well with a 40-45% decrease in renal peroxidatic activity of cytochrome P450 in hamsters treated with these substances plus estradiol for 1 month. In addition, these compounds also inhibited the oxidation of diethylstilbestrol to its corresponding quinone in vitro. An influence on quinone reductase or other detoxifying enzymes in chronically treated male Syrian hamsters could not be detected. These data support a mediation of estradiol-induced carcinogenesis by quinones formed by metabolic oxidation of catechol estrogens.


Metabolomic analyses to evaluate the effect of drought stress on selected African Eggplant accessions.
Drought stress is one of the main abiotic stresses that affect crops. It leads to biochemical changes that can have adverse effects on plant growth, development and productivity. African eggplants are important vegetable and fruit crops reported to adapt and thrive well under drought stress. The diversified metabolites arising due to stress have not been well defined. A gas chromatographic-mass spectrometric metabolomic approach was applied to characterize the effect of drought stress on metabolites at different stages of growth. Nineteen accessions were selected for analysis and drought was imposed by withholding water until soil moisture reached 60% field capacity. Fresh leaf tissues were sampled before stress, 2 and 4 weeks after stress and metabolite profiling done. Significant changes in metabolite content were observed, and potentially important metabolites with respect to stress responses were characterized. Proline, glutamate, sucrose, fructose and tricarboxylic acid cycle metabolites were shown to be positively correlated with stress. Principal component analysis showed a clear discrimination between the different accessions, growth stages and stress/control conditions. The results illustrate that drought stress has a significant impact on the concentrations of some metabolites, such as amino acids, sugars and organic acids, which may contribute to drought stress effects and tolerance. © 2017 Society of Chemical Industry.


Stimulation of hematopoiesis in vivo by recombinant bacterial murine interleukin 3.
Mouse interleukin 3 (IL-3) cDNA was cloned into a plasmid construction, allowing the synthesis of very high quantities of IL-3 in Escherichia coli. The recombinant (r) IL-3, purified to homogeneity, was active in vitro on the proliferation and differentiation of various hematopoietic progenitor cells at 1 pM. To maintain detectable blood levels of IL-3, osmotic pumps containing rIL-3 or control solutions were placed under the skin of normal and irradiated C3H/HeJ and (BALB X B10) F1 mice. The effect of IL-3 on hematopoietic progenitor cell numbers in spleen and bone marrow was evaluated 3 and 7 days later by using an in vitro clonal assay. The results demonstrated the following: (i) Doses of IL-3 infused at the rate of 2.5-5 ng per g of body weight per hr were sufficient to increase the numbers of hematopoietic progenitors in normal mice by at least 2-fold within 3 days. (ii) In mice with progenitor cell levels depressed by sublethal irradiation, 7-day treatment with IL-3 resulted in a 10-fold increase to near normal levels. (iii) The erythroid and myeloid lineages appeared to be enhanced to the same extent. (iv) Enhancement of hematopoiesis occurred primarily in spleen, but hematopoietic foci were also evident in the liver; in contrast, total cell and progenitor cell numbers were decreased in the bone marrow.


A clinical, cytogenetic and molecular study of ten probands with supernumerary inv dup (15) marker chromosomes.
Ten probands with moderate to severe developmental delay were found to have a supernumerary inv dup (15) chromosome. These patients and their families were studied by both cytogenetic and molecular methods. Cytogenetic polymorphisms associated with the 15p short arm suggested a maternal derivation for the marker chromosome in all informative cases. One marker was directly maternally inherited. Molecular analysis employing Southern blotting and polymerase chain reaction (PCR) of microsatellite repeats demonstrated the presence of extra alleles in the 15q11q13 region. All ten of the probands demonstrated an extra band at one or more locus without recourse to densitometry. All of the inv dup (15) markers were comparable in size to a G group chromosome but there were differences in the positions of the breakpoints in 15q. There was an inconsistent relationship between marker size, gene dosage and severity of phenotype.


Dacryocytes are a common morphologic feature of autoimmune and microangiopathic haemolytic anaemia.
Dacryocytes are teardrop-shaped erythrocytes which are most frequently observed in peripheral blood smears of patients with primary or secondary myelofibrosis as well as malignant infiltrative disorders of the bone marrow. Dacryocytes have rarely been described in blood smears of patients with autoimmune (AIHA) and microangiopathic haemolytic anaemia (MAHA). The clear prevalence of dacryocytes in AIHA and MAHA is unknown. We compared the dacryocyte counts in blood smears stained according to the May-Grünwald-Giemsa technique between 20 subjects with AIHA and MAHA with those from 21 controls. The dacryocytes, defined as erythrocytes tapered to a point at one end, were counted as cells per 20 high power fields (HPF) at 630-fold magnification. In AIHA, MAHA and controls, dacryocytes were found in 89%, 91% and 19% of the slides, respectively. The rate of dacryocyte positivity and the dacryocyte counts between haemolytic anaemias and controls differed statistically highly significant (p<0.0001). The results of this study indicate that dacryocytes are commonly apparent in blood smears of patients with AIHA and MAHA. Knowledge of this frequent feature may be beneficial in clinical routine diagnosis.


Exploring whole-genome duplicate gene retention with complex genetic interaction analysis.
Whole-genome duplication has played a central role in the genome evolution of many organisms, including the human genome. Most duplicated genes are eliminated, and factors that influence the retention of persisting duplicates remain poorly understood. We describe a systematic complex genetic interaction analysis with yeast paralogs derived from the whole-genome duplication event. Mapping of digenic interactions for a deletion mutant of each paralog, and of trigenic interactions for the double mutant, provides insight into their roles and a quantitative measure of their functional redundancy. Trigenic interaction analysis distinguishes two classes of paralogs: a more functionally divergent subset and another that retained more functional overlap. Gene feature analysis and modeling suggest that evolutionary trajectories of duplicated genes are dictated by combined functional and structural entanglement factors.


Retinal vessel oxygen saturation in healthy subjects and early branch retinal vein occlusion.
To measure the retinal oxygen saturation in healthy subjects and early branch retinal vein occlusion (BRVO) in Chinese population. The retinal vessel oxygen saturation of the healthy subjects and BRVO patients were measured by a noninvasive retinal oximeter (Oxymap ehf., Reykjavik, Iceland). The study included 22 patients with unilateral BRVO (mean age: 55.1±8.8y) in the study group and 91 healthy participants (mean age: 37.5±14.0y) in the control group. In the healthy individuals, mean arterial and venous oxygen saturation were significantly (P<0.001) higher in the superior nasal quadrant (98.5%±10.1% and 57.3%±8.7%, respectively) than in the inferior nasal quadrant (94.2%±9.0% and 54.1%±9.6%, respectively), followed by the superior temporal quadrant (89.1%±10.1% and 51.9%±8.9%, respectively) and the inferior temporal quadrant (86.4%±9.4% and 46.6%±9.6%, respectively). In patients with ischemic BRVO, arterial oxymetric values were significantly higher and venous measurements significantly lower for the affected vessel (107.5%±9.7% and 46.4%±14.2%, respectively) than the unaffected vessel in the same eye (99.2%±12.2% and 55.5%±7.9%, respectively) and as compared to the vessel in the unaffected fellow eye (93.1%±6.9% and 55.7%±6.8%) (P=0.005 and P=0.02, respectively). In the patients with non-ischemic BRVO, mean venous oxygen saturation was lower in the affected vein (39.8%±12.2%) than in the unaffected vessels of the same eye (50.8%±10.5%) and in the fellow eye (58.21%±5.7%) (P=0.03). Mean arterial oxygen saturation did not differ significantly (P=0.42) between all three groups. In patients with BRVO, the venous oxygen saturation in the affected vessels is decreased potentially due to decreased blood velocity and flow. Interestingly, the arterial oxygen saturation in eyes with ischemic BRVO is increased in the affected arteries.


Pharmacogenetics of inflammatory bowel disease.
Pharmacogenetic studies have been performed for almost all classes of drugs that have been used in IBD but very few have generated consistent findings or have been replicated. The genetic test that has been approved for clinical practice is TPMT testing prior to starting treatment with thiopurine drugs. Research in IBD pharmacogenetics has focused on prediction of drug efficacy and toxicity by identifying polymorphisms in the genes encoding enzymes that are involved in metabolic pathways. Recent research has mainly focused on therapeutic agents such as azathioprine, methotrexate, aminosalicylates, corticosteroids, infliximab and adalimumab. Future pharmaceutical trials should include pharmacogenetic research to test appropriate candidate genes in a prospective manner and correlate genetic associations with trial outcomes and relevant functional data.


Enhancement and modification of etoposide release from crospovidone particles loaded with oil-surfactant blends.
A novel solid formulation for oral delivery of pH-sensitive, scarcely water-soluble etoposide has been designed, characterized, and tested in vitro. The purpose of this study was to assess the performance of the new dosage forms, in comparison to marketed, liquid-filled capsules. The solid formulation was developed by grinding the drug with a cross-linked polymeric carrier (crospovidone) under controlled process conditions (mechano-physical drug activation), and subsequently incorporating selected oil/surfactant (o/s) blends into the polymer particles. Physicochemical characterization (thermal analysis, drug dissolution kinetics, drug o/w partition studies) provided information on drug-polymer interaction at the solid state, and on the formulation performance in vitro, resulting in the enhancement and modification of the etoposide solubilization process. DSC thermograms showed the amorphous or nanocrystalline state of etoposide within the carrier, as indicated by the shifting of DSC peaks (delta T > -10 degrees C). Solubility kinetics of etoposide in oversaturation conditions were strongly affected by the chemical nature of the vehicle used: short-chain triglycerides afforded drug concentrations well above 600 micrograms ml-1 for more than 3 hr, versus a drug equilibrium solubility of approximately 150 micrograms ml-1. Drug dissolution curves under sink conditions were superimposable to those of liquid-filled capsules available on the market (Vepesid 50, Bristol-Myers Squibb), yielding 100% drug release in 10 min. The oil phase/water partition coefficient of etoposide (P) was affected by the surfactant concentration. The biphasic trend observed in P values suggested a dual mechanism in drug release from polymeric particles: the presence of oily vehicles and surfactants in the formulation could create, upon release, a favorable environment to sustain etoposide dissolution, slowing down drug reprecipitation. Such solid formulation could be considered equivalent, in vitro, to the current marketed product.


CTLL assay: comparison of two methods for IL-2 determination.
Two different modifications of CTLL techniques for IL-2 detection, the routine 3II-thymidine incorporation assay and the colorimetric MTT method, were compared. The reproducible results of the studies of supernatants from in vitro propagated transfected cells were obtained. The employed methods appeared to be comparable and are used simultaneously in our co-operating laboratories for estimation of the levels of IL-2 secreted by the transfectants that are applied as the source of the cytokine in therapeutic experiments.


Impact of Konjac Glucomannan with Different Molecular Weight on Retrogradation Properties of Pea Starch.
The impact of konjac glucomannan (KGM) with different molecular weight (Mw) on the retrogradation properties of pea starch, such as color, viscoelasticity, gel strength, water holding capacity (WHC), moisture distribution and crystallinity, was investigated. At the same time as the Mw of KGM decreased, the lightness, elastic modulus, gel strength, water freedom and crystallinity of pea starch showed an increasing trend, whereas the viscosity modulus and WHC showed a decreasing trend. At one day of storage, compared with single pea starch, KGM with low Mw made gel strength increase from 40 g to 45 g, WHC decrease from 82% to 65% and crystallinity increase from 21.3% to 24.0%. Therefore, KGM with low Mw could promote retrogradation of pea starch in the short-term. At 7 days or even 14 days of storage, KGM with medium-high Mw had smaller indices than those of pure pea starch, including the lightness, storage modulus, gel strength, water freedom and crystallinity. This indicated that KGM with medium-high Mw could inhibit the long-term retrogradation of starch. The larger the Mw of KGM, the more noticeable the inhibition effect.


The ionization energy of Be2, and spectroscopic characterization of the (1)3Sigmau+, (2)3Pig, and (3)3Pig states.
Low lying electronic states of the beryllium dimer were investigated by laser induced fluorescence (LIF) and resonance enhanced multiphoton ionization (REMPI) techniques. Be(2) was formed by pulsed laser ablation of Be metal in the presence of helium carrier gas, followed by a free jet expansion into vacuum. Several previously unobserved states of the dimer were characterized. These included transitions of the triplet manifold (2)(3)Pi(g) <-- (1)(3)Sigma(u)+ and (3)(3)Pi(g) <-- (1)(3)Sigma(u)+, for which rotationally resolved bands were obtained. In addition, transitions to the v' = 10-18 vibrational levels of the A (1)Pi(u) state were recorded. Photoionization efficiency (PIE) measurements were used to determine an accurate ionization energy (IE) for Be(2) of 7.418(5) eV and the term energy for (1)(3)Sigma(u)+. Above the ionization threshold the PIE spectrum was found to be highly structured, consisting of overlapping Rydberg series that converged on excited vibrational levels of Be(2)+. Analysis of these series yielded a vibration frequency for the X(2)Sigma(u)+ state of 498(20) cm(-1). The bond dissociation energy for Be(2)+, deduced from the IE measurement, was 16 072(40) cm(-1). Multi-reference configuration interaction (MRCI) calculations were carried out for Be(2) and Be(2)+, yielding results that were in excellent agreement with the experimental observations.


The smoking habits of men with intermittent claudication.
Smoking habits among 54 male patients with intermittent claudication (IC) and 200 healthy 50-year-old men from the same county have been studied. The prevalence of smokers at the age of 50 was 98% among the IC patients against 46% among the healthy controls. The percentage of heavy smokers and the total tobacco consumptiion were not significantly different in the two groups. However, the percentage of smokers who began to smoke before the age of 15 was significantly higher in IC patients than in the healthy group, 28% to 7%.


Experimental and Computational Approaches to Improve Binding Affinity in Chemical Biology and Drug Discovery.
Drug discovery is one of the most complicated processes and establishment of a single drug may require multidisciplinary attempts to design efficient and commercially viable drugs. The main purpose of drug design is to identify a chemical compound or inhibitor that can bind to an active site of a specific cavity on a target protein. The traditional drug design methods involved various experimental based approaches including random screening of chemicals found in nature or can be synthesized directly in chemical laboratories. Except for the long cycle design and time, high cost is also the major issue of concern. Modernized computer-based algorithm including structure-based drug design has accelerated the drug design and discovery process adequately. Surprisingly from the past decade remarkable progress has been made concerned with all area of drug design and discovery. CADD (Computer Aided Drug Designing) based tools shorten the conventional cycle size and also generate chemically more stable and worthy compounds and hence reduce the drug discovery cost. This special edition of editorial comprises the combination of seven research and review articles set emphasis especially on the computational approaches along with the experimental approaches using a chemical synthesizing for the binding affinity in chemical biology and discovery as a salient used in de-novo drug designing. This set of articles exfoliates the role that systems biology and the evaluation of ligand affinity in drug design and discovery for the future.


Analysis of Hospitalization after Peritoneal Dialysis Catheter Implantation.
♦ Implantation of the peritoneal dialysis catheter (PDC), usually an elective procedure, may necessitate unexpected hospitalization and even transfer to intensive care due to the multiple comorbidities and inherent instability of the end-stage renal disease patient. Information on hospitalization after PDC implantation is limited and details about the reason for hospitalization are lacking. ♦ We performed a cohort study in consecutive patients who underwent PDC implantation at a single institution from September 2007 to September 2013. Clinical characteristics of enrolled patients, technique of the implantation procedure, and all-cause unexpected hospitalization and morbidity within 14 days after implantation were analyzed. ♦ Excluding the patients with pre-arranged admission, a total of 246 patients receiving 252 PDC implantations during the 6 years were studied. After 39 procedures (15.5%), patients had an unexpected hospital stay or re-admission due to operative complications (33.3%), worsening of disease (35.9%), or a single-night hospital stay for observation (30.8%). Compared with discharged patients, the patients with unexpected hospitalization were older (p = 0.001), experienced higher rates of previous episodes of heart failure (p = 0.006) and heart disease (p < 0.001), had more use of general anesthesia (GA) (p = 0.046), underwent more added procedures during the implantation (p = 0.02), and had more episodes of flow obstruction and peritonitis after implantation (p = 0.012 and p < 0.001, respectively). Using a multivariable logistic regression, we showed that age, cardiac morbidity, use of general anesthesia, PDC flow problems and peritonitis after implantation were independent predictors of all-cause unexpected hospitalization. ♦ For the first time, our study analyzed the predictors of unplanned hospitalization after PDC implantation and identified the salient risk factors. Increased focus to identify patients at greatest risk for hospitalization, evaluation of processes of care, and implementation of preventive strategies may be helpful to reduce unplanned hospitalization after catheter insertion.


CRISPR/Cas9 targeting events cause complex deletions and insertions at 17 sites in the mouse genome.
Although CRISPR/Cas9 genome editing has provided numerous opportunities to interrogate the functional significance of any given genomic site, there is a paucity of data on the extent of molecular scars inflicted on the mouse genome. Here we interrogate the molecular consequences of CRISPR/Cas9-mediated deletions at 17 sites in four loci of the mouse genome. We sequence targeted sites in 632 founder mice and analyse 54 established lines. While the median deletion size using single sgRNAs is 9 bp, we also obtain large deletions of up to 600 bp. Furthermore, we show unreported asymmetric deletions and large insertions of middle repetitive sequences. Simultaneous targeting of distant loci results in the removal of the intervening sequences. Reliable deletion of juxtaposed sites is only achieved through two-step targeting. Our findings also demonstrate that an extended analysis of F1 genotypes is required to obtain conclusive information on the exact molecular consequences of targeting events.


The thermal work limit is a simple reliable heat index for the protection of workers in thermally stressful environments.
Workers in many industries are exposed to thermally stressful work environments. Protection of the health of workers without unnecessarily compromising productivity requires the adoption of a heat index that is both reliable and easy to use. To evaluate the Thermal Work Limit (TWL), in a controlled environment and under field conditions, against these criteria. Volunteers performed graded work in a controlled thermal environment to determine the limiting workload for the conditions. Core temperature and heart rate were monitored as indicators of thermoregulation. In the field study, outdoor workers were monitored for signs of physiological strain in thermal environments which were characterized using both the traditional Wet Bulb Globe Temperature (WBGT) and the TWL. Abilities of each of these indices to accurately reflect the thermal stress on workers were evaluated. In the controlled environment, the TWL was found to reliably predict the limiting workload. In the field study, TWL was a more appropriate and realistic index than WBGT, which was found to be excessively conservative. The results confirm previously published studies evaluating TWL in underground environments, which have led to its widespread adoption in the Australian mining industry. The study extends the applicability of TWL to outdoor environments and generates management guidelines for its implementation.


Chaplaincy and mental health care in aotearoa New Zealand: an exploratory study.
This paper summarizes an initial exploratory study undertaken to consider the ministry of New Zealand chaplaincy personnel working within the mental health care context. This qualitative research (a first among New Zealand mental health care chaplains) was not concerned with specific health care institutions per se, but solely about the perspectives of chaplains concerning their professional contribution and issues they experienced when trying to provide pastoral care to patients, families, and clinical staff involved in mental health care. Data from a single focus group indicated that chaplains were fulfilling various WHO-ICD-10AM pastoral interventions as a part of a multidisciplinary and holistic approach to mental health care; however, given a number of frustrations identified by participants, which either impeded or thwarted their professional role as chaplains, a number of improvements were subsequently identified in order to develop the efficiency and effectiveness of chaplaincy and thus maximize the benefits of pastoral care to patients, families, and clinical staff. Some implications of this exploratory study relating to mental health care chaplaincy, ecclesiastical organizations, health care institutions, and government responsibilities and the need for further research are noted.


Antithrombotic treatment failures in antiphospholipid syndrome: the new anticoagulants?
Anticoagulation with oral vitamin K antagonists (VKA) is the mainstay of the treatment of venous and/or arterial thromboembolism in patients with antiphospholipid syndrome (APS), although the optimal intensity of anticoagulation remains controversial. The limitations of existing anticoagulants have driven a search for novel agents. Dabigatran etexilate (Pradaxa), a direct thrombin inhibitor (DTI), and rivaroxaban (Xarelto), the first in a new class of drugs, the oral direct factor Xa (FXa) inhibitors, are both fixed-dose orally administered agents. They are now licensed in the UK and Europe for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective total hip replacement (THR) or total knee replacement (TKR). Prospective randomized clinical trials suggest that these agents, and also apixaban, a further oral direct anti-Xa inhibitor, may have potential in other areas including the treatment of acute VTE, prevention of stroke or systemic embolism in patients with atrial fibrillation (AF) and acute coronary syndromes. Here, we summarize current indications for these agents and address the potential for their use in patients with thrombotic APS.


Hydatid disease of the spine: A rare case.
Hydatid disease or hydatidosis is the most widespread zoonosis caused by Echinococcus granulosus. Liver and lungs are the most common sites. Bone involvement is rare and reported in 0.5%-4% with spinal involvement reported in 50% of these cases. We present a case of spinal hydatidosis in a 35-year-old male presenting with lower extremity weakness and numbness. Magnetic resonance imaging (MRI) of the spine showed multiple cystic lesions at the T9-T11 level with involvement of the paraspinal muscles. The lesion was seen intraspinal, intradural, intramedullary, and epidural. Radiological impression was aneurysmal bone cyst. The patient underwent laminectomy, and the excised cysts showed characteristic features of hydatid cyst (HC) on histopathology. The patient was started on antihelminthic therapy postoperatively. MRI is a diagnostic modality for HC, but the unusual location and absence of characteristic features can cause diagnostic difficulty. A high index of suspicion should be kept in patients residing in endemic areas and presenting with unusual cystic lesion of spine.


You don't know me, but I know you: the illusion of asymmetric insight.
People, it is hypothesized, show an asymmetry in assessing their own interpersonal and intrapersonal knowledge relative to that of their peers. Six studies suggested that people perceive their knowledge of their peers to surpass their peers' knowledge of them. Several of the studies explored sources of this perceived asymmetry, especially the conviction that while observable behaviors (e.g., interpersonal revelations or idiosyncratic word completions) are more revealing of others than self, private thoughts and feelings are more revealing of self than others. Study 2 also found that college roommates believe they know themselves better than their peers know themselves. Study 6 showed that group members display a similar bias-they believe their groups know and understand relevant out-groups better than vice versa. The relevance of such illusions of asymmetric insight for interpersonal interaction and our understanding of "naive realism" is discussed.


Growth performance, blood health, antioxidant status and immune response in red sea bream (Pagrus major) fed Aspergillus oryzae fermented rapeseed meal (RM-Koji).
This study evaluated the effects of dietary substitution of fishmeal by graded levels of a blend composed of Aspergillus oryzae fermented rapeseed meal [0% (RM0), 25% (RM25), 50% (RM50), 75% (RM75) and 100% (RM100)] on growth performance, haemato-immunological responses and antioxidative status of Pagrus major (average weight 5.5 ± 0.02 g). After 56 days, growth performances were significantly improved in fish fed RM25 diet compared to control (P < 0.05). Meanwhile, up to 50% replacement of fishmeal did not affect growth performance, feed conversion efficiency, protein efficiency ratio, protein apparent digestibility, protease activity, fish somatic indices and survival compared to control. While blood hematocrit and plasma protein were significantly enhanced in groups fed RM0 and RM25 diets, most of the hematological parameters did not change through the trial except glutamic pyruvate transaminase which was significantly increased in RM75 and RM100 groups and blood cholesterol which was gradually decreased with the increasing level of the blend. Interestingly, feeding fish with RM25 and RM50 diets significantly showed enhanced lysozyme, bactericidal and peroxidase activities and fish fed the same diets showed high resistance against oxidative stress (biological antioxidant potential and reactive oxygen metabolites). Additionally, catalase activity and tolerance against low salinity seawater were higher in fish fed RM25 diet. These findings suggested that, at a moderate level (25% and 50%), substitution of fishmeal by the fermented rapeseed meal promoted growth, nutrient utilization, and exerted immune responses and anti-oxidative effects in red sea bream.


Grasping beer mugs: on the dynamics of alignment effects induced by handled objects.
We examined automatic spatial alignment effects evoked by handled objects. Using color as the relevant cue carried by an irrelevant handled object aligned or misaligned with the response hand, responses to color were faster when the handle aligned with the response hand. Alignment effects were observed only when the task was to make a reach and grasp response. No alignment effects occurred if the response involved a left-right key press. Alignment effects emerged over time, becoming more apparent either when the color cue was delayed or when relatively long, rather than short, response times were analyzed. These results are consistent with neurophysiological evidence indicating that the cued goal state has a modulatory influence on sensorimotor representations, and that handled objects initially generate competition between neural populations coding for a left- or right-handed action that must be resolved before a particular hand is favored.


Interval Squamous Cell Carcinoma of the Rectum.
Squamous cell carcinoma (SCC) of the rectum is a rare clinical entity with an incidence rate of 0.1-0.25% per 1,000 cases. Though its etiology and pathogenesis remains unclear, it has been associated with chronic inflammation and infections. Herein, we report a case of an 82-year-old female who presented with a 2-month history of worsening abdominal pain, hematochezia, and bilateral inguinal lymphadenopathy with right-sided purulent discharge. Two years prior, she had had an unremarkable screening colonoscopy which met all quality indicators. Abdominal CT scan showed an irregular rectal mass with bulky pelvic and retroperitoneal adenopathy. Colonoscopy revealed one large circumferential nonobstructing lesion in the rectum. Endoscopic ultrasound confirmed its origin from the rectal wall with an enlarged perirectal lymph node. Cold biopsy followed by histopathology revealed SCC of the rectum.


Alloplastic Auricular Reconstruction: Review of Implant Types, Adverse Events, and Aesthetic Outcomes.
Alloplastic implants have been applied successfully in reconstruction of the external ear, either for congenital microtia or traumatic injury. The objective of this study was to conduct a comprehensive systematic review of alloplastic implant materials utilized in the reconstruction of the external ear stratified by indication, specific implant type, postoperative complications, and aesthetic outcomes. A comprehensive systematic review of published literature on alloplastic external ear reconstruction data was conducted utilizing Medline/PubMed database without timeframe limitations in June 2019. Articles were stratified by (1) indication (microtia versus trauma reconstruction) and (2) implant material type. All postoperative complications were recorded and comparatively analyzed between implant types. Aesthetic outcomes were also identified and compared between implant types. A total of 755 patients (14 case series; follow-up range = 3 months--10 years) met the criteria for this study. Overall complication rate was 12.05% across all indications and materials used. The most frequent complications reported were graft exposure (7.8%), graft explantation (1.72%), and wound dehiscence (0.8%). Of the patients requiring graft explantation (n = 13), 7 (53.85%) received Medpor implants, and the other 6 (46.15%) were identified in silicone implants. Infection was only reported in Medpor implants. The overall rate of an acceptable aesthetic outcome was 99.34%. Alloplastic implants are a reliable means of achieving an acceptable complication profile in external ear reconstruction. While there was an overall high rate of acceptable aesthetic outcomes, the studies evaluated in this systematic review differed in their criteria for final evaluation of aesthetic outcomes.


The role of CFTR and SPINK-1 mutations in pancreatic disorders in HIV-positive patients: a case-control study.
Pancreatic disorders in HIV-positive patients are frequent. CFTR and SPINK-1 mutations have been reported to increase the risk of pancreatitis, but no data are available in HIV-positive patients. This study will evaluate the frequency of CFTR mutations and SPINK-1 polymorphisms in HIV-positive patients with clinical pancreatitis or asymptomatic elevation of serum pancreatic enzymes. Cases (patients with hyperamylasemia) were identified during a toxicity study conducted in August 1999 among 1152 participants of the Swiss HIV Cohort Study. We designed a case-control study in which each case was matched one to one to an HIV-infected control according to sex, age, CD4 cell count, viraemia and medication use. CFTR mutations and SPINK-1 polymorphisms were studied using polymerase chain reaction techniques. Fifty-one HIV-positive patients with hyperamylasemia were detected among 1152 participants in the toxicity study (4.4%). There were 13 carriers of CFTR and SPINK-1 mutations (12.7%). Amylase levels were 316 +/- 130 U/l for the group with mutations, and 135 +/- 18 U/l for non-carriers (P = 0.79). However, among patients with hyperamylasemia, those with CFTR or SPINK-1 mutations had 648 +/- 216 U/l amylase levels compared with 232 +/- 28 U/l for those without (P = 0.025). Ten patients had acute pancreatitis, four of whom had CFTR mutations or SPINK-1 polymorphisms (40%) compared with seven of the control patients (14%) (P = 0.01). CFTR mutations and SPINK-1 polymorphisms are frequent among HIV-positive patients suffering from acute pancreatitis. These mutations may increase the susceptibility to pancreatitis when exposed to environmental risk factors.


Quasiclassical determination of reaction probabilities as a function of the total angular momentum.
This article presents a quasiclassical trajectory (QCT) method to determine the reaction probability as a function of the total angular momentum J for any given value of the initial rotational angular momentum j. The proposed method is based on a discrete sampling of the total and orbital angular momenta for each trajectory and on the development of equations that have a clear counterpart in the quantum-mechanical (QM) case. The reliability of the method is illustrated by comparing QCT and time-dependent wave-packet QM results for the H+D(2)(upsilon=0,j=4,10) reaction. The small discrepancies between both sets of calculations, when they exist, indicate some genuine quantum effects. In addition, a procedure to extract the reaction probabilities as a function of J when trajectories are calculated in the usual way using a continuous distribution of impact parameters is also described.


Case Report: Camrelizumab combined with gemcitabine and oxaliplatin in the treatment of advanced intrahepatic cholangiocarcinoma: a case report and literature review.
Intrahepatic cholangiocarcinoma (ICC) is one of the most common invasive malignant tumors, with a 5-year survival rate of less than 5%. Currently, radical surgical resection is the preferred treatment for ICC. However, most patients are only diagnosed at an advanced stage and are therefore not eligible for surgery. Herein, we present a case of advanced ICC in which radical surgery was not possible due to tumor invasion of the second porta hepatis and right hepatic artery. Six treatment cycles with a gemcitabine and oxaliplatin (GEMOX) regimen combined with camrelizumab immunotherapy achieved a partial response and successful tumor conversion, as tumor invasion of the second porta hepatis and right hepatic artery was no longer evident. The patient subsequently underwent successful radical surgical resection, including hepatectomy, caudate lobe resection, and cholecystectomy combined with lymph node dissection. Cases of patients with advanced ICC undergoing surgical resection after combined immunotherapy and chemotherapy are rare. The GEMOX regimen combined with camrelizumab demonstrated favorable antitumor efficacy and safety, suggesting that it might be a potential feasible and safe conversion therapy strategy for patients with advanced ICC.


Mononeuropathy of the deep palmar branch of the ulnar nerve. A case occurring in a diabetic woman.
A diabetic woman developed mononeuropathy of the deep palmar branch of the ulnar nerve six months following repetitive palmar trauma. The illness was initially incorrectly diagnosed as motor neuron disease, emphasizing the importance of accurate diagnosis of diseases that cause wasting of intrinslc muscles in the hand.


Structure and energetics in the complexes of a double-stranded B-DNA dodecamer with netropsin derivatives of a tricationic water-soluble porphyrin: a theoretical investigation.
The structural and energetical characteristics of the complexes formed between two auto-complementary DNA dodecamers, d(CGCGAATTCGCG)2, and d(GCGCAATTGCGC)2, and two novel netropsin (I) and glycine-netropsin (II) conjugates of a tricationic water-soluble porphyrin are investigated in detail by means of theoretical computations. This study was prompted by the successful chemical synthesis of II, which was recently reported (Anneheim-Herbelin, G., Perrée-Fauvet, M., Gaudemer, A., Hélissey, P., Giorgi-Renault, S. and Gresh, N., Tetrahedron Lett. 34, 7263 (1993)). The results indicate that: a) Intercalative binding of II does not entail significant distortions of the DNA backbone, and the Net moiety can bind tightly to the core of the minor groove. b) Intercalative binding of I is computed to energetically weaker than that of II. This is a consequence of the reduced length of the oligopeptide arm, such that the terminal propionamidinium group interacts less favorably with the fourth A-T base-pair than is the case with II. c) Nonintercalative binding of II produces considerable conformational distortions of the DNA. These results in a break of the DNA axis in between the fourth and the fifth base-pairs, namely, at the level where the long axis of the chromophore and of the oligopeptide intersect.


Dual activation of cardiac sympathetic and parasympathetic components during conditioned fear to context in the rat.
1. The present study investigates the contribution of the sympathetic and vagal parasympathetic systems to the tachycardic response of long-lasting (40 min) conditioned fear responses to context. 2. The conditioned fear response evoked by re-exposure to a footshock chamber was tested 10 min after intravenous injection of the beta-adrenoceptor antagonist propranolol (2 mg/kg) or the muscarinic antagonist atropine methyl nitrate (2 mg/kg) in rats implanted with radiotelemetric probes. 3. Compared with saline controls, the drugs did not change the behavioural component of the response (freezing, 22 kHz ultrasonic vocalizations) or its pressor component (+28 mmHg). 4. Propranolol abolished the tachycardic response of fear, whereas atropine more than doubled it (from +75 to +175 b.p.m. above resting baseline). 5. The results demonstrate that both sympathetic and vagal parasympathetic outflows to the heart are strongly activated during conditioned fear. The vagal activation may act to hold back cardiac acceleration while the animal waits for the aversive stimulus to come.


Incorporation of an iterative, linear segmentation routine into a mammographic mass CAD system.
In previous research, we have developed a computer-aided detection (CAD) system designed to detect masses in mammograms. The previous version of our system employed a simple but imprecise method to localize the masses. In this research, we present a more robust segmentation routine for use with mammographic masses. Our hypothesis is that by more accurately describing the morphology of the masses, we can improve the CAD system's ability to distinguish masses from other mammographic structures. To test this hypothesis, we incorporated the new segmentation routine into our CAD system and examined the change in performance. The developed iterative, linear segmentation routine is a gray level-based procedure. Using the identified regions from the previous CAD system as the initial seeds, the new segmentation algorithm refines the suspicious mass borders by making estimates of the interior and exterior pixels. These estimates are then passed to a linear discriminant, which determines the optimal threshold between the interior and exterior pixels. After applying the threshold and identifying the object's outline, two constraints on the border are applied to reduce the influence of background noise. After the border is constrained, the process repeats until a stopping criterion is reached. The segmentation routine was tested on a study database of 183 mammographic images extracted from the Digital Database for Screening Mammography. Eighty-three of the images contained 50 malignant and 50 benign masses; 100 images contained no masses. The previously developed CAD system was used to locate a set of suspicious regions of interest (ROIs) within the images. To assess the performance of the segmentation algorithm, a set of 20 features was measured from the suspicious regions before and after the application of the developed segmentation routine. Receiver operating characteristic (ROC) analysis was employed on the ROIs to examine the discriminatory capabilities of each individual feature before and after the segmentation routine. A statistically significant performance increase was found in many of the individual features, particularly those describing the mass borders. To examine how the incorporation of the segmentation routine affected the performance of the overall CAD system, free-response ROC (FROC) analysis was employed. When considering only malignant masses, the FROC performance of the system with the segmentation routine appeared better than the previous system. When detecting 90% of the malignant masses, the previous system achieved 4.9 false positives per image (FPpI) compared to the post-segmentation system's 4.2 FPpI. At 80% sensitivity, the respective FPpI were 3.5 and 1.6.


Color and orientation are jointly coded and spatially organized in primate primary visual cortex.
Previous studies support the textbook model that shape and color are extracted by distinct neurons in primate primary visual cortex (V1). However, rigorous testing of this model requires sampling a larger stimulus space than previously possible. We used stable GCaMP6f expression and two-photon calcium imaging to probe a very large spatial and chromatic visual stimulus space and map functional microarchitecture of thousands of neurons with single-cell resolution. Notable proportions of V1 neurons strongly preferred equiluminant color over achromatic stimuli and were also orientation selective, indicating that orientation and color in V1 are mutually processed by overlapping circuits. Single neurons could precisely and unambiguously code for both color and orientation. Further analyses revealed systematic spatial relationships between color tuning, orientation selectivity, and cytochrome oxidase histology.


Oxygen consumption and central hemodynamics in septic shock treated with antibiotics, fluid infusions, and corticosteroids.
The multidimensional pathophysiology of septic shock is poorly understood and treatment modalities are controversial. The present study evaluates the relative importance of three therapeutic measures: antibiotics (trimethoprim and sulphamethoxazole [TS]); fluid infusions (lactated Ringer's solution [RL] and 3% albumin [Alb]), and pharmacologic doses of corticosteroids (CS) (dexamethasone [DM]), using central hemodynamics (plasma volume [PV], cardiac output, oxygen consumption [VO2]), and survival as end-points. Septic shock was induced by intraperitoneal injection of live Escherichia coli bacteria. At 5 h in untreated septic rats, PV had dropped to 76%, cardiac output to 69%, and VO2 to 71% of preshock levels. Untreated septic animals had a mean survival time of 9.7 +/- 1.7 (SD) h, with none surviving 24 h. Regardless of therapy, cardiac output and VO2 at 10 h were predictors of survival time (p less than .01). Treatment was initiated at 5.5 h after bacterial injection, at a time when TS therapy alone had not improved the 24-h survival rate. Animals treated with DM, RL, and Alb, in this order, exhibited progressively improved central hemodynamics, and 24-h survival rate increased to 60% compared with 0 in untreated animals (p less than .001). The combination of DM and RL produced no further improvement. However, DM combined with 3% Alb restored VO2, cardiac output, and PV to 81%, 100%, and 125%, respectively, increasing the 24-h survival rate to 97% (29/30), significantly greater than that achieved by any other treatment modality (p less than .05).


Projection-based polygonality measurement.
Measuring the degree to which a shape resembles a polygon (referred to as polygonality) is a difficult problem due to the intrinsic diversity in the form and distortion of shapes caused by digitization and similarity transformation. This paper proposes a generic approach for this problem by performing the measurement in the projection space where the Radon image of some primitive shapes, which compose the shape, becomes apparent. The obtained measures take value in (0, 1] with 1 corresponding to analytical polygons. They are robust to additive noise and boundary distortion, and is invariant to similarity transformation. The new framework generalizes existing polygonal measures such as triangularity and quadrangularity. In addition, the ability to estimate polygon's geometric quantities in the projection space allows approximating a shape by analytical polygons. The efficiency of the proposed approach is demonstrated through a number of experiments on both synthetic and real data sets.


SOFT Syndrome: The First Case in Iran.
Primordial dwarfism (PD) is a group of rare genetically heterogeneous disorders consisted of disorders with intrauterine growth retardation continued through the life. SOFT syndrome with characteristics of short stature, onychodysplasia, facial dysmorphism, and hypotrichosis has been presented as a subtype of PD. Only 20 cases of SOFT syndrome have been reported in world to date, but none of them were not in Iran. Our case was 6.5-year-old girl with a complaint of growth retardation including height of 97 cm (Z = -4.6 standard deviation [SD]) and weight of 14 kg (Z = -4 SD) referred to growth clinic. She had a prominent forehead, triangular face, short limbs, malformed nails, and crowded teeth and her psychomotor function was normal. Laboratory and karyotype tests were normal while she was homozygous for c.G491A mutation of POC1A gene thus SOFT syndrome diagnosis was confirmed for her and recombinant growth hormone therapy was discontinued.


Effect of antiepileptic drug comedication on lamotrigine clearance.
To investigate the effect of antiepileptic drug (AED) comedication, including all newer AEDs, on lamotrigine clearance (CL). We reviewed 570 medical charts of outpatients 12 years and older seen at the Columbia Comprehensive Epilepsy Center who received lamotrigine as monotherapy or adjunctive therapy. We investigated whether a given comedication contributed to the lamotrigine serum concentration. In addition, we examined whether the mean lamotrigine CL during comedication with each AED differed from the lamotrigine CL during monotherapy. Finally, we examined whether individuals had significantly different lamotrigine CLs when taking or not taking a particular comedication. Comedication with phenytoin, carbamazepine, and valproate sodium were the major AED predictors of lamotrigine serum concentration. Comedication regimens with felbamate, oxcarbazepine, and phenobarbital were small but significant predictors. The mean lamotrigine CL was 43.2 mL/h per kilogram of body weight with lamotrigine monotherapy, significantly higher with comedication with phenytoin (101.3 mL/h per kilogram) and carbamazepine (59.5 mL/h per kilogram) and significantly lower with valproate (16.9 mL/h per kilogram). Patients had significantly higher lamotrigine CL when taking phenytoin, carbamazepine, and phenobarbital than when not taking those comedications and had significantly lower lamotrigine CL when taking valproate. The mean lamotrigine CL was significantly lower than that associated with monotherapy in patients comedicated with valproate plus phenytoin (22.0 mL/h per kilogram) but not in patients comedicated with valproate plus carbamazepine (33.3 mL/h per kilogram). No other AEDs affected lamotrigine CL. Phenytoin increases lamotrigine CL by approximately 125%, carbamazepine increases lamotrigine CL by approximately 30% to 50%, and valproate decreases lamotrigine CL by approximately 60%. No newer AED, with the possible exception of oxcarbazepine, has a major impact on lamotrigine CL.


The Mesothelial Origin of Carcinoma Associated-Fibroblasts in Peritoneal Metastasis.
Solid tumors are complex and unstructured organs that, in addition to cancer cells, also contain other cell types. Carcinoma-associated fibroblasts (CAFs) represent an important population in the tumor microenviroment and participate in several stages of tumor progression, including cancer cell migration/invasion and metastasis. During peritoneal metastasis, cancer cells detach from the primary tumor, such as ovarian or gastrointestinal, disseminate through the peritoneal fluid and colonize the peritoneum. Tumor cells metastasize by attaching to and invading through the mesothelial cell (MC) monolayer that lines the peritoneal cavity, then colonizing the submesothelial compact zone where CAFs accumulate. CAFs may derive from different sources depending on the surrounding metastatic niche. In peritoneal metastasis, a sizeable subpopulation of CAFs originates from MCs through a mesothelial-to-mesenchymal transition (MMT), which promotes adhesion, invasion, vascularization and subsequent tumor growth. The bidirectional communication between cancer cells and MC-derived CAFs via secretion of a wide range of cytokines, growth factors and extracellular matrix components seems to be crucial for the establishment and progression of the metastasis in the peritoneum. This manuscript provides a comprehensive review of novel advances in understanding how peritoneal CAFs provide cancer cells with a supportive microenvironment, as well as the development of future therapeutic approaches by interfering with the MMT in the peritoneum.


Bronchiolitis obliterans after allogeneic hematopoietic SCT: further insight--new perspectives?
Bronchiolitis obliterans (BO) is a late non-infectious pulmonary complication after allogeneic hematopoietic SCT. Among 982 patients after myeloablative hematopoietic SCT between January 2000 and October 2010, 68 were diagnosed with BO according to NIH criteria. The median onset of BO was 18 months post transplant, 5-year cumulative incidence was 5.8% and 5-year mortality 41%. BO prevalence rate was 10% among all long-term surviving hematopoietic SCT recipients and 12% among chronic GVHD-patients. Chronic GVHD, peripheral SCT and ABO blood group incompatibility were identified as risk factors associated with BO. IgG levels were significantly decreased at the onset of BO (6.7 g/L±0.7, P=0.001), the mean exhaled NO concentrations were lower in BO-patients than in stem cell recipients without BO (14 p.p.b.±0.9 vs 20 p.p.b.±2.1) or healthy controls (25 p.p.b.±2.4, P<0.001). Hypoxia-inducible factor 1 alpha (HIF-1α) was significantly elevated in BO as compared with healthy controls or GVHD-patients without lung involvement (340±61 vs 127±22 vs 140±32, P=0.02). Calculated 5-year survival was superior in female than in male BO-patients (86 vs 45%, P=0.04). These results emphasize the relevance of BO as serious late complication with substantial mortality and point to essential pathophysiological changes due to regulatory responses to hypoxia.


Genome maintenance and transcription integrity in aging and disease.
DNA damage contributes to cancer development and aging. Congenital syndromes that affect DNA repair processes are characterized by cancer susceptibility, developmental defects, and accelerated aging (Schumacher et al., 2008). DNA damage interferes with DNA metabolism by blocking replication and transcription. DNA polymerase blockage leads to replication arrest and can gives rise to genome instability. Transcription, on the other hand, is an essential process for utilizing the information encoded in the genome. DNA damage that interferes with transcription can lead to apoptosis and cellular senescence. Both processes are powerful tumor suppressors (Bartek and Lukas, 2007). Cellular response mechanisms to stalled RNA polymerase II complexes have only recently started to be uncovered. Transcription-coupled DNA damage responses might thus play important roles for the adjustments to DNA damage accumulation in the aging organism (Garinis et al., 2009). Here we review human disorders that are caused by defects in genome stability to explore the role of DNA damage in aging and disease. We discuss how the nucleotide excision repair system functions at the interface of transcription and repair and conclude with concepts how therapeutic targeting of transcription might be utilized in the treatment of cancer.


Reviewing the concept of Dahl.
Toothwear may have a multifactorial aetiology but is often localized to the upper anterior teeth. This is normally accompanied by a loss of interocclusal space. This paper aims to outline the management of localized anterior toothwear. It discusses several options available to create space for anterior restoration, with particular reference to the use of the 'Dahl' technique. Dahl described a non-invasive technique to create increased interocclusal space. The increased space eliminates the need for further occlusal reduction during crown preparation which is ideal in the worn dentition. This paper illustrates and describes the clinical applications of Dahl's original technique.


Can pelvic floor muscle training improve sexual function in women with pelvic organ prolapse? A randomized controlled trial.
Pelvic floor muscle training (PFMT) has level 1 evidence of reducing the size and symptoms associated with pelvic organ prolapse (POP). There is scant knowledge, however, regarding whether PFMT has an effect on sexual function. The aim of the trial was to evaluate the effect of PFMT on sexual function in women with POP. In this randomized controlled trial, 50 women were randomized to an intervention group (6 months of PFMT and lifestyle advice) and 59 women were randomized to a control group (lifestyle advice only). Participants completed a validated POP-specific questionnaire to describe frequency and bother of prolapse, bladder, bowel, and sexual symptoms and answered a semi-structured interview. No significant change in number of women being sexually active was reported. There were no significant differences between groups regarding change in satisfaction with frequency of intercourse. Interview data revealed that 19 (39%) of women in the PFMT group experienced improved sexual function vs. two (5%) in the control group (P<0.01). Specific improvements reported by some of the women were increased control, strength and awareness of the pelvic floor, improved self-confidence, sensation of a "tighter" vagina, improved libido and orgasms, resolution of pain with intercourse, and heightened sexual gratification for partners. Women who described improved sexual function demonstrated the greatest increases in pelvic floor muscle (PFM) strength (mean 16 ± 10 cmH2 0) and endurance (mean 150 ± 140 cmH2 0s) (P<0.01). PFMT can improve sexual function in some women. Women reporting improvement in sexual function demonstrated the greatest increase in PFM strength and endurance.


Anti-Microbial Resistance In Pakistan: A Public Health Issue
Anti-microbial or antibiotic resistance is a global public health problem, more dominant in the developing countries. Illiteracy and lack of awareness among the general population is a leading cause, compounded by lack of concern by the physicians and the pharmacists selling drugs over the counter. Another side of the phenomenon is attributed to profit making goals of pharmaceutical companies and weak regulation of the market. Nevertheless, misuse and overuse of antimicrobials accelerates this process. Besides, health issues, anti-microbial resistance also has economic implications on the health care system, where the simpler treatments are becoming difficult, day by day. Enforcement of standard treatment guidelines for the health providers and behavior changes at the patients' end are likely to bring about a change in the situation.


Assessment of emetine cardiotoxicity in a subacute toxicity experiment in rats.
We explored the usefulness of cardiovascular function studies for the detection and characterization of emetine cardiotoxicity in a subacute toxicity experiment. Rats received 1 mg/kg, s.c., emetine five times weekly for up to 7 weeks. In unanesthetized animals, statistically significant changes of the electrocardiogram (EKG) appeared in the following sequence: prolongation of QRS interval (5th day), flattening of T wave (beginning of 4th week), and prolongation of PR interval (end of 4th week). Terminal cardiovascular studies were conducted under urethane anesthesia. EKG changes were comparable to those recorded in conscious rats, but no decrease in T wave voltage occurred. Blood pressure and heart rate remained unchanged. Cardiac output was decreased after 5 and 7 weeks of treatment, when heart weights were also significantly reduced. The response of cardiac output and mean arterial blood pressure to intravenously injected norepinephrine and epinephrine remained unchanged. Catecholamine-induced arrhythmias occurred less frequently in emetine-treated animals than in controls. No significant structural lesions of the heart muscle were detected by light microscopy. The cardiotoxic effects observed in rats were similar to those reported in humans receiving the usual therapeutic dose of approximately 1 mg/kg/day. We conclude that cardiovascular function studies can make an important contribution to the predictive value of animal toxicity experiments.


Fusing multiple neuroimaging modalities to assess group differences in perception-action coupling.
In the last few decades, non-invasive neuroimaging has revealed macro-scale brain dynamics that underlie perception, cognition and action. Advances in non-invasive neuroimaging target two capabilities; 1) increased spatial and temporal resolution of measured neural activity, and 2) innovative methodologies to extract brain-behavior relationships from evolving neuroimaging technology. We target the second. Our novel methodology integrated three neuroimaging methodologies and elucidated expertise-dependent differences in functional (fused EEG-fMRI) and structural (dMRI) brain networks for a perception-action coupling task. A set of baseball players and controls performed a Go/No-Go task designed to mimic the situation of hitting a baseball. In the functional analysis, our novel fusion methodology identifies 50ms windows with predictive EEG neural correlates of expertise and fuses these temporal windows with fMRI activity in a whole-brain 2mm voxel analysis, revealing time-localized correlations of expertise at a spatial scale of millimeters. The spatiotemporal cascade of brain activity reflecting expertise differences begins as early as 200ms after the pitch starts and lasting up to 700ms afterwards. Network differences are spatially localized to include motor and visual processing areas, providing evidence for differences in perception-action coupling between the groups. Furthermore, an analysis of structural connectivity revealed that the players have significantly more connections between cerebellar and left frontal/motor regions, and many of the functional activation differences between the groups are located within structurally defined network modules that differentiate expertise. In short, our novel method illustrates how multimodal neuroimaging can provide specific macro-scale insights into the functional and structural correlates of expertise development.


[Lung cancer diagnosis based on urinary modified nucleoside metabolic profiling].
To study the feasibility of modified urinary nucleosides metabolic profiling on lung cancer diagnoses. The modified urinary nucleosides metabolic profiling from 42 normal adults and 80 patients with lung cancer were determined by a coupled-column high performance liquid chromatography system. Partial least squares-discriminant analysis (PLS-DA) models were used to class differentiation between the lung cancer patients and controls and to discover potential biomarkers. The PLS-DA model results showed that there was a clear differentiation between normal adults and lung cancers patients, with the value of prediction (Q2) equals to 0.744. Modified urinary nucleosides metabolic profiling method is useful for lung cancer diagnoses.


Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway.
Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, ATO produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive ATO treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases Chk1, Chk2 and p53 levels were increased, as were levels of activated ATM and γ-H2AX. The cell viability was decreased as an ATM inhibitor was added. Additionally, these effects of ATO on γ-H2AX, Chk1, Chk2, p53, and p21(waf1/cip1) were reduced by an ATM inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive.


Suspicions of titanium allergic reaction influencing the prosthetic solution in a rare case of implant "flowering".
The aim of this paper is to eliminate suspicions of a titanium (Ti) allergy in a rare case of "flowered" implant in a 43-year-old female patient with metal allergies and no history of bruxism, using a histological and immunohistochemical (IHC) analysis to determine the phenotype of cells that participated in the immune response; also, to assess the prognosis of a future implant treatment and to highlight the psychological impact of osseointegrated implant failure caused by fracture, and the influence that the necessity to use extensive surgical procedures for reimplantation can have on the treatment solution chosen by the patient. The results of our IHC analysis did not indicate a clear response for a potential Ti allergy; still, due to psychological reasons, the patient rejected the replantation and considered the use of other restorative option, a three-unit bridge, as being the most appropriate for her. Considering her opinion and attitude, the fixed prosthetic denture assured the therapeutic success.


Increasing students' physical activity during school physical education: rationale and protocol for the SELF-FIT cluster randomized controlled trial.
The Self-determined Exercise and Learning For FITness (SELF-FIT) is a multi-component school-based intervention based on tenets of self-determination theory. SELF-FIT aims to increase students' moderate-to-vigorous physical activity (MVPA) during physical education lessons, and enhance their autonomous motivation towards fitness activities. Using a cluster randomized controlled trial, we aim to examine the effects of the intervention on students' MVPA during school physical education. Secondary 2 students (approximately aged 14 years) from 26 classes in 26 different schools will be recruited. After baseline assessments, students will be randomized into either the experimental group or wait-list control group using a matched-pair randomization. Teachers allocated to the experimental group will attend two half-day workshops and deliver the SELF-FIT intervention for 8 weeks. The main intervention components include training teachers to teach in more need supportive ways, and conducting fitness exercises using a fitness dice with interchangeable faces. Other motivational components, such as playing music during classes, are also included. The primary outcome of the trial is students' MVPA during PE lessons. Secondary outcomes include students' leisure-time MVPA, perceived need support from teachers, need satisfaction, autonomous motivation towards physical education, intention to engage in physical activity, psychological well-being, and health-related fitness (cardiorespiratory and muscular fitness). Quantitative data will be analyzed using multilevel modeling approaches. Focus group interviews will also be conducted to assess students' perceptions of the intervention. The SELF-FIT intervention has been designed to improve students' health and well-being by using high-intensity activities in classes delivered by teachers who have been trained to be autonomy needs supportive. If successful, scalable interventions based on SELF-FIT could be applied in physical education at large. The trial is registered at the Australia New Zealand Clinical Trial Registry (Trial ID: ACTRN12615000633583 ; date of registration: 18 June 2015).


Angiotensin I-Converting Enzyme (ACE) Inhibition and Molecular Docking Study of Meroterpenoids Isolated from Brown Alga, Sargassum macrocarpum.
Angiotensin I-converting enzyme (ACE) is an important blood pressure regulator. In this study, we aimed to investigate the ACE-inhibitory effects of meroterpenoids isolated from the brown alga, Sargassum macrocarpum, and the molecular mechanisms underlying ACE inhibition. Four fractions of S. macrocarpum were prepared using hexane, chloroform, ethyl acetate, and water as solvents and analyzed for their potential ACE-inhibitory effects. The chloroform fraction showed the strongest ACE-inhibitory effect, with an IC50 value of 0.18 mg/mL. Three meroterpenoids, sargachromenol, 7-methyl sargachromenol, and sargaquinoic acid, were isolated from the chloroform fraction. Meroterpenoids isolated from S. macrocarpum had IC50 values of 0.44, 0.37, and 0.14 mM. The molecular docking study revealed that the ACE-inhibitory effect of the isolated meroterpenoids was mainly attributed to Zn-ion, hydrogen bonds, pi-anion, and pi-alkyl interactions between the meroterpenoids and ACE. These results suggest that S. macrocarpum could be a potential raw material for manufacturing antihypertensive nutraceutical ingredients.


The Effect of Epicatechin-(4β-8)-Catechin on Some Biomarkers of Fatigue in Packed Donkeys (Equus Asinus) during the Dry Season in Northern Nigeria.
Overworking and overloading of donkeys may cause fatigue. The experiment aims to determine the effects of epicatechin-(4β-8)-catechin (EEC) on some fatigue biomarkers in packed donkeys during the dry season. 10 jacks, aged between four and five years were used for the study. Five were given EEC in feed seven days before packing (test), while another five were given feed only (control). Blood samples collected for biochemical analyses were analyzed for superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), total antioxidant capacity (TAC), creatine kinase (CK) and tumor necrosis factor-alpha (TNF-α). The SOD activity increased significantly (P < 0.05) in the test group during the cold-dry season after packing. The values of TAC during the packing period were significantly (P < 0.05) higher in test group during the hot-dry season. The TNF-α concentration was higher (P > 0.05) in the control group especially one-hour on route. The CK activity was significantly (P < 0.05) higher in the control donkeys during the hot-dry season. In conclusion, packing donkeys during the dry season resulted in fatigue, but EEC served as an anti-fatigue agent.


A pocket companion to cell-free DNA (cfDNA) preanalytics.
The cumulative pool of cell-free DNA (cfDNA) molecules within bodily fluids represents a highly dense and multidimensional information repository. This "biological mirror" provides real-time insights into the composition, function, and dynamics of the diverse genomes within the body, enabling significant advancements in personalized molecular medicine. However, effective use of this information necessitates meticulous classification of distinct cfDNA subtypes with exceptional precision. While cfDNA molecules originating from different sources exhibit numerous genetic, epigenetic, and physico-chemical variations, they also share common features that complicate analyses. Considerable progress has been achieved in mapping the landscape of cfDNA features, their clinical correlations, and optimizing extraction procedures, analytical approaches, bioinformatics pipelines, and machine learning algorithms. Nevertheless, preanalytical workflows, despite their profound impact on cfDNA measurements, have not progressed at a corresponding pace. In this perspective article, we emphasize the pivotal role of robust preanalytical procedures in the development and clinical integration of cfDNA assays, highlighting persistent obstacles and emerging challenges.


[Leadless pacemakers: results of a survey from implanter centers in the Lombardy region].
Transvenous pacing is nowadays the cornerstone of interventional management of bradyarrhythmias. It is still associated, however, with significant complications, mostly related to indwelling transvenous leads or device pocket. In order to reduce these complications, leadless pacemakers have been recently introduced into clinical practice, but no guidelines are yet available to indicate who are those patients that might benefit the most and whether leadless pacing should be preferred in the old or young population. This survey aims to describe the use of leadless pacemaker devices in a real-world setting. Eleven arrhythmia centers in the Lombardy region (out of a total of 17 participating centers) responded to the proposed questionnaire regarding patient characteristics and indications to leadless pacing. Out of a total of 411 patients undergoing leadless pacing during 4.2 ± 0.98 years, the median age was 77 years, with 0.18% of patients having less than 18 years, 29.9% 18-65 years, 34.3% 65-80 years and 35.6% >80 years. The most common indication was slow atrial fibrillation (49% of patients), followed by atrioventricular block and sinoatrial dysfunction. Two centers reported in-hospital complications. Leadless pacemakers proved to be a safe pacing strategy actually destined mostly to elderly patients.