A novel role for SIRT-1 in L-arginine protection against STZ induced myocardial fibrosis in rats.
L-arginine (L-ARG) effectively protects against diabetic impediments. In addition, silent information regulator (SIRT-1) activators are emerging as a new clinical concept in treating diabetic complications. Accordingly, this study aimed at delineating a role for SIRT-1 in mediating L-ARG protection against streptozotocin (STZ) induced myocardial fibrosis. Male Wistar rats were allocated into five groups; (i) normal control rats received 0.1 M sodium citrate buffer (pH 4.5); (ii) STZ at the dose of 60 mg/kg dissolved in 0.1 M sodium citrate buffer (pH 4.5); (iii) STZ + sirtinol (Stnl; specific inhibitor of SIRT-1; 2 mg/Kg, i.p.); (iv) STZ + L-ARG given in drinking water (2.25%) or (v) STZ + L-ARG + Stnl. L-ARG increased myocardial SIRT-1 expression as well as its protein content. The former finding was paralleled by L-ARG induced reduction in myocardial fibrotic area compared to STZ animals evidenced histopathologically. The reduction in the fibrotic area was accompanied by a decline in fibrotic markers as evident by a decrease in expression of collagen-1 along with reductions in myocardial TGF-β, fibronectin, CTGF and BNP expression together with a decrease in TGF-β and hydroxyproline contents. Moreover, L-ARG increased MMP-2 expression in addition to its protein content while decreasing expression of PAI-1. Finally, L-ARG protected against myocardial cellular death by reduction in NFκ-B mRNA as well as TNF-α level in association with decline in Casp-3 and FAS expressions andCasp-3protein content in addition to reduction of FAS positive cells. However, co-administration of L-ARG and Stnl diminished the protective effect of L-ARG against STZ induced myocardial fibrosis. Collectively, these findings associate a role for SIRT-1 in L-ARG defense against diabetic cardiac fibrosis via equilibrating the balance between profibrotic and antifibrotic mediators.


A Norwalk-like virus outbreak on the Appalachian Trail.
In May and June 1999, an outbreak of acute gastrointestinal illness occurred among long-distance hikers on the Appalachian Trail between Catawba and Troutville, Virginia. An investigation found that 45 out of 70 hikers had become ill within two days of arriving in Catawba, Virginia. Water samples were collected from a general store frequented by the hikers and from several nearby buildings and a popular all-you-can-eat restaurant. Symptoms were consistent with those caused by Norwalk-like viruses, and laboratory diagnosis detected Norwalk-like viruses in stool and serum specimens. People who consumed food items prepared at the general store were almost twice as likely to become ill as persons who did not consume those foods. Environmental sampling of water from the taps inside and outside the general store and from several surrounding establishments in Catawba found contamination by fecal coliform bacteria but not by Norwalk-like virus. Since several hikers reported illness prior to arriving at Catawba, person-to-person transmission of a highly contagious agent such as Norwalk-like virus could not be ruled out. Poor sanitation, scarce water supplies, and crowding can increase the risk of gastrointestinal illness among long-distance hikers.


Successful treatment of Klebsiella rhinoscleromatis bacteremia with levofloxacin.
A 71-year-old Caucasian woman was admitted to the hospital with right-sided weakness and slurred speech. Glioblastoma multiforme was diagnosed, and resection of the tumor was performed. During the patient's hospitalization, blood and urine cultures were obtained after her temperature rose to 103.3 degrees F. Four blood cultures revealed Klebsiella rhinoscleromatis sensitive to trimethoprim-sulfamethoxazole, levofloxacin, cefazolin, gentamicin, and tetracycline, but resistant to ampicillin. The patient had no recent history of foreign travel. After a 3-week course with levofloxacin, the patient was afebrile, and repeat blood cultures were negative. To our knowledge, this was the first case of K. rhinoscleromatis bacteremia in the United States to be treated successfully with levofloxacin.


Does ambulance response time influence patient condition among patients with specific medical and trauma emergencies?
The relation between patient outcome and ambulance response times is unknown. We sought to measure the influence of shorter response times on patient outcomes. The objective of the study was to determine whether ambulance response time makes a difference in the outcomes of emergency medical services (EMS) patients with specific traumatic and medical emergencies. This study was conducted in a metropolitan EMS system serving a population of 800,000, including urban and rural areas. Cases were included if the private EMS service was the first medical provider on scene, the case was priority 1, and the patients were 13 years old and older. A 14-month time period was used for the data evaluation. Four diagnoses were examined: motor vehicle crash injuries, penetrating trauma, difficulty breathing, and chest pain complaints. Data collected included ambulance response times, initial vital signs, and the number of vital signs out of range. Cases seen at the single major trauma center were selected for evaluation of hospital outcome. Correlation coefficients were used to evaluate interactions between independent and outcome variables. Of the 2164 cases we reviewed, the EMS service responded significantly faster to trauma complaints at 4.5 minutes (n = 254) than medical complaints at 5.9 minutes (n = 1910). In the trauma center sample of 559 cases, response time was not related to hospital days (P = 0.5), admissions (P = 0.7), intensive care unit admissions (P = 0.4), or deaths (P = 0.3). This study showed that in cases seen at a major trauma center, longer response times were not associated with worse outcomes for the diagnostic groups tested.


Serum potassium variability as a predictor of clinical outcomes in patients with cardiorenal disease or diabetes: a retrospective UK database study.
Hyperkalaemia is an electrolyte abnormality associated with adverse clinical outcomes; however, few studies have investigated the relationship with patterns of hyperkalaemia over time. This study explored the impact of time spent in a hyperkalaemic state and variability of serum potassium (sK+) on major adverse cardiovascular events (MACE) and all-cause mortality in patients with chronic kidney disease (CKD), resistant hypertension, heart failure and diabetes. Cohorts comprised adult patients diagnosed with CKD stage 3+, resistant hypertension, heart failure or diabetes, and/or renin-angiotensin-aldosterone system inhibitor prescription, between 1 January 2003 and 30 June 2018, from the UK Clinical Practice Research Datalink. Associations between percentage of follow-up spent in a hyperkalaemic state (sK+ ≥5.0 mmol/L, ≥5.5 mmol/L, ≥6.0 mmol/L) or sK+ variability (standard deviation above or below median standard deviation) and all-cause mortality or MACE were investigated. For sK+ ≥5.0 mmol/L, time spent in a hyperkalaemic state was associated with reduced risk of all-cause mortality across all cohorts. For higher sK+ thresholds, this trend was attenuated or reversed; for time spent in a hyperkalaemic state at sK+ ≥6.0 mmol/L, an increased risk of mortality was seen in the overall cohort and for patients with diabetes, resistant hypertension or prescribed renin-angiotensin-aldosterone system inhibitors, with no consistent association seen for patients with CKD or heart failure. Risk of MACE in the overall cohort and in patients with CKD, diabetes or resistant hypertension increased with time spent in a hyperkalaemic state at all sK+ thresholds; however, no correlation was seen in patients with heart failure or those receiving dialysis. High sK+ variability was associated with a higher risk of MACE compared with low sK+ variability across most sK+ categories in the overall population and in all disease cohorts, except patients on dialysis; however, no association between sK+ variability and all-cause mortality was observed. Patterns of hyperkalaemia, including time spent in hyperkalaemia and sK+ variability, are associated with adverse clinical outcomes. Regular monitoring of sK+ in high-risk populations in broader community, primary care and outpatient settings may enable guideline-recommended management of hyperkalaemia and help avoid adverse events.


[Hepatotoxicity of perfluorooctanoic acid in human hepatocytes using metabonomics].
Ultra performance liquid chromatography coupled to orthogonal acceleration time-of-flight mass spectrometry was used to study metabolic profiling of L-02 human liver cell exposed to different doses of perfluorooctanoic acid (PFOA) for 72 h. Principle component analysis method was used for group differentiation and biomarker screening. Dose-dependent distribution of the treated samples with different doses could be observed in scores plots obtained under both positive and negative ionization modes. Furthermore, eighteen metabolites were identified as potential biomarkers which were closely related with the toxicity of PFOA. The identified biomarkers included carnitine and acylcarnitines, nucleosides and nucleoside conjugates, amino acids and amino acid conjugates etc. Among them, significant changes of carnitine and its metabolites were observed in the control group and dose groups, which play an important role in fatty acid metabolism. Meanwhile, some genes involved in cholesterol biosynthesis were upregulated dramatically using gene microarray analysis. The disturbance of cholesterol biosynthesis could have adverse impact on fatty acid metabolism, consequently induce the decrease of carnitine and increase of acylcarnitines in treated groups. Additionally, purine metabolism, tricarboxylic acid cycle, glycosphingolipid metabolism and amino acid metabolism may also be involved in the toxic response to PFOA.


An excellent example illustrating the fluorescence sensing property of cobalt-organic frameworks.
A novel luminescent cobalt-organic framework was assembled and employed as a chemosensor for the detection of metal ions via fluorescence enhancement and quenching. The sensing mechanism was based on the exposed pyridyl and carboxyl functional sites in the MOF structure, which interacted with metal ions via Lewis acid-base interactions and electrostatic interactions.


Duplication 6q24: More Than Just Diabetes.
Chromosome 6q24-related transient neonatal diabetes mellitus is characterized by intrauterine growth restriction and low birth weight, with neonatal hyperglycemia resolving by 18 months and an increased risk for type 2 diabetes in adulthood. Molecularly, it is caused by overexpression of the 6q24 imprinted chromosomal region due to a duplication, uniparental disomy, or abnormal methylation. Conventional testing for this condition analyzes methylation patterns at the 6q24 locus but does not evaluate for the presence of other surrounding chromosomal abnormalities. We report a female with a history of neonatal hyperglycemia due to a paternally inherited duplication at chromosomal location 6q24. She subsequently presented to the pediatric genetics clinic at 15 months of age with developmental delay and abnormal balance. Microarray analysis identified a larger 14 Mb chromosomal duplication from 6q24 to 6q25.2, consistent with a diagnosis of duplication 6q syndrome. This case highlights the clinical importance of pursuing further genetic evaluation in patients diagnosed with chromosome 6q24-related neonatal hyperglycemia via targeted methylation-specific multiplex ligation-dependent probe amplification analysis identifying a duplication in this region. Early identification and intervention can improve developmental outcomes for patients with larger chromosome 6q duplications.


[Molecular logic of alcohol and taste].
Ethanol, a main constituent of every alcohol beverage, has long been calling our attention to its gustatory effect. Recent molecular dynamics studies have suggested that ethanol as well as other tastants in foods, when taken in the oral cavity, gives rise to a taste signal which is expressed via reception at taste cells in the taste bud, intracellular signal transduction in collaboration with G proteins and effecters, and signal transmission to synapsed taste neurons, and/or simultaneous reception at and signal transduction in somatosensory neurons. The taste of ethanol and its acceptability are then recognized and judged at the higher center, with generation of various physiological phenomena in the body. We have tried to make an all-inclusive DNA microarray analysis, demonstrating that when a rat tongue is stimulated with a drop of aqueous ethanol in vivo, several particular genes are specifically up- or down-regulated in trigeminal ganglions. These initial gene expression changes at peripheral neurocytes might in whole or in part trigger some of the ethanol-associated gustatory and bodily response. The importance of defining a related molecular logic is emphasized to understand academic and industrial significances of this unique food constituent, ethanol.


Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite.
A molecular modeling study giving structural, functional, and mutagenesis insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite is reported. Our results allow extending experimental data resulting from X-ray diffraction experiments in order to examine unknown aspects for the Fab-BACE1 recognition and its binding mode. Thus, the study performed here allows extending the inherently static nature of crystallographic structures in order to gain a deeper understanding of the structural and dynamical basis at the atomic level. The characteristics and strength of the interatomic interactions involved in the immune complex formation are exhaustively analyzed. The results might explain how the anti-BACE1 Fab fragment and other BACE1 exosite binders are capable to produce an allosteric modulation of the BACE1 activity. Our site-directed mutagenesis study indicated that the functional anti-BACE1 paratope, residues Tyr32 (H1), Trp50 (H2), Arg98 (H3), Phe101 (H3), Trp104 (H3) and Tyr94 (L3), strongly dominates the binding energetics with the BACE1 exosite. The mutational studies described in this work might accelerate the development of new BACE1 exosite binders with interesting pharmacological activity.


The case for excision in the treatment of brain abscess.
A historical review of the literature of brain abscess is made and an examination of the universally high mortality and morbidity figures achieved in the past, mainly with conventional burrhole aspiration. A series of 50 cases of supratentorial brain abscess treated over a period of 12 years by immediate primary excision, is presented with discussion. Mortality rate, including patients in coma on admission, was 6%. Morbidity in survivors was correspondingly low.


Myositis in primary Sjögren's syndrome: clinical and pathological report.
Abstract To clarify the clinical features of myositis complicated with primary Sjögren's syndrome (SS), we studied 89 patients with Sjögren's syndrome (one male and 88 females; mean age 56.0 ± 15.31 years). Myositis was diagnosed from clinical findings, muscle enzymes, electromyographic findings, and muscle biopsy findings. Myositis was diagnosed in 5 of 89 SS patients (5.6%). One patient developed myositis 7 months after the onset of SS. The other four patients were diagnosed with myositis and SS simultaneously. Muscular weakness was mild and slowly progressive over 4-14 months (mean 8.4 months). All patients were able to walk without any assistance at the start of prednisolone therapy. Muscular enzymes were slightly elevated (from 1.5- to 12-fold). All patients tested negative for anti-Jo1 antibody and tested positive for antinuclear antibody. Anti-Ro(SSA) antibody was positive in 4/5 (90%); anti-La(SSB) was positive in 2/5 (40%). Although the clinical features of all patients met the criteria for polymyositis of Bohan, they responded well to small or moderate doses of prednisolone, which could be decreased without a recurrence of muscular weakness in all patients. Myositis with Sjögren's syndrome showed relatively moderate symptoms and responded well to prednisolone. A prospective follow-up of patients may provide further information.


Urocortin expression in mouse cochlear nucleus and Scarpa's ganglion.
Clinical and basic studies have correlated tinnitus with stress. Although the etiology of tinnitus is unknown, the cochlear nucleus (CN) appears to play a role. To better understand the potential impact of stress on tinnitus and modulation of the central auditory system in general, the goal of the current study was to examine the presence and distribution of axon terminals containing urocortin in the CN of the mouse. Prospective description of histological findings. Three different forms of urocortin were labeled in brainstem sections collected from 10 wild-type mice by immunohistochemistry. Immunoreactive terminal fibers in the CN were digitally photographed, as well as reconstructed in the CN under a drawing tube attached to a light microscope. Specific staining was found in en passant type fibers scattered throughout the CN but situated mostly within the granule cell domains. Clusters of labeled fibers were observed in the nerve root. Labeled axons were observed in the three tracts known to carry olivocochlear fibers to the CN, as well as in the olivocochlear bundle itself. As the axons within the olivocochlear bundle departed the brainstem in the vestibular nerve, numerous labeled en passant fibers were observed among somata of the vestibular ganglion (Scarpa's). Centrally, labeled axons were followed from the CN to the lateral superior olive, an established source of urocortin-positive efferents to the cochlea. These findings indicate that lateral olivocochlear efferents innervate the CN and Scarpa's ganglion, and also that urocortin is likely a neuromodulator in particular CN circuits. The current study supports innervation of specific regions of the mouse CN and Scarpa's ganglion by neurons expressing urocortin. The innervation may be one substrate by which stress modulates particular CN processes. Further studies are necessary to establish the role of urocortin in CN models of tinnitus.


[Cutaneous reconstruction at the leg and foot level. Experience in 277 clinical cases].
The authors present their clinical experience of leg and foot reconstruction with 227 clinical cases. Based on these cases the authors analyse the use of 18 musculocutaneous, 53 axial, 72 septocutaneous and 84 free flaps, totalling 29 different kinds of flaps performed. Although no definitive conclusions can be drawn about which are the best flaps for foot and leg reconstruction, the preferential options are pointed out.


Pharmacokinetics, efficacy, and safety of cannabidiol in dogs: an update of current knowledge.
In the last 5 years, interest has grown in using phytocannabinoids, particularly cannabidiol (CBD), in veterinary medicine to treat several pathologies, including pain, epilepsy, anxiety, nausea, anorexia, skin lesions, and even some types of cancer, among others. Indeed, due to a positive perception of CBD use, many pet owners are increasingly requesting this option to relieve their pets, and many veterinarians are exploring this possibility for their patients. Besides the widespread empiric use of CBD in pets, the research is trying to obtain proof of its efficacy and lack of adverse effects and to know its pharmacokinetics to define an appropriate posology. This review summarizes all data published so far about the canine pharmacokinetics, efficacy, and tolerability of CBD and cannabidiolic acid (CBDA). Despite a certain number of available pharmacokinetic studies, the kinetic profile of CBD has yet to be fully known, probably because of the very different experimental conditions. In terms of efficacy, most studies have tested CBD' ability to relieve osteoarthritic pain. In contrast, few studies have evaluated its role in epilepsy, behavioral disorders, and skin lesions. From obtained results, some evidence exists supporting the beneficial role of CBD. Nevertheless, the limited number of published studies and the occurrence of bias in almost all require caution in interpreting findings. From tolerability studies, CBD' side effects can be classified as mild or unremarkable. However, studies were prevalently focused on short- to medium-term treatment, while CBD is usually employed for long-term treatment. Further studies are warranted to define better whether CBD could be a valid adjunct in canine treatment.


Effects of pyridinolcarbamate on the cardiovascular system of the anesthetized dog after bilateral cervical vagotomy.
Pyridinolcarbamate (PDC) was injected at a dose of 10 mg/Kg of body weight into the femoral vein of anesthetized dogs with a bilateral cervical vagosympathotomy. At this dose, it produced a transitory decrease in systolic, diastolic, and mean arterial pressure and an increase in heart rate. In addition, it produced a more prolonged increase in stroke volume, peak aortic flow, cardiac output, and left ventricular minute work. It also lowered peripheral resistance and apparently decreased the vaso-constrictor action of injected norepinephrine (1 mug of active base/Kg of body weight). These data are consistent with the view that PDC has a direct action on the heart that is similar to that of norepinephrine and that PDC blocks the alpha adrenergic receptors of the systemic resistance vessels.


The current use and future trends of focal surgical therapy in the management of localized prostate cancer.
The current treatment algorithms for management of localized prostate cancer are mainly extirpative in nature. Treatment varies from expectant management to radical prostatectomy or radiation therapy. However, the ever-increasing emphasis on achieving the best survival benefit while better preserving quality of life, coupled with the introduction of new, safer, and efficacious minimally invasive ablative technologies, has led to the increased popularity of minimally invasive treatment (MIT). MIT refers to the use of a wide range of techniques for local target ablation of the prostate gland with minimal damage to the surrounding tissue. Currently these include cryotherapy and high-intensity focused ultrasound. However, other experimental technologies such as photodynamic therapy, interstitial prostate brachytherapy, and microwave and radiofrequency interstitial tumor ablation are also currently under investigation in early clinical trials. To date, the overall interim results for these relatively new modalities of treatment appear comparable to those for surgical and radiation therapies. However, randomized, controlled studies are needed to support use of these modalities as an alternative to surgery and radiation. In this review, we will address the current rationale for and knowledge of MIT with regard to its safety and efficacy in the treatment of localized prostate cancer. In addition, we will discuss future promising tools in MIT such as photodynamic therapy and the target focal therapy approach as a new trend for the treatment of organ-confined low-volume disease.


Characterization and nucleotide sequence of two herpes simplex virus 1 genes whose products modulate alpha-trans-inducing factor-dependent activation of alpha genes.
Herpes simplex viruses encode a structural protein which induces, in trans, expression of alpha genes, the first set of genes to be expressed after infection of permissive cells. This protein, designated as the alpha-trans-inducing factor (alpha-TIF), maps within the BamHI F fragment, and its gene has been sequenced. In the course of mapping the domain of the alpha-TIF gene, it was noted that the intact BamHI fragment was consistently more effective than the complete domain of the alpha-TIF gene in inducing expression of alpha genes. Cotransfections of DNA fragments containing an alpha indicator gene and the alpha-TIF gene with various regions of the BamHI F DNA fragment revealed that the sequences located 3' to the alpha-TIF gene raised the activity of the alpha-TIF gene to nearly the same level as that of the intact BamHI F fragment. The nucleotide sequence and S1 nuclease mapping analyses revealed the presence of two transcribed open reading frames capable of encoding polypeptides with translated molecular weights of 77,357 and 70,527. To determine whether the effect of these sequences in trans on alpha-TIF-mediated induction of alpha genes was due to expression of these genes or competition for transcriptional factors, we constructed plasmids that contained both genes. Into each or both of these genes we inserted, near the translation initiation sites, 14-base-pair linkers carrying translational stop codons (TAG) in all three reading frames. Analyses of these plasmids indicated that the gene encoding the 70,527-molecular-weight polypeptide reduced alpha-TIF-dependent induction of alpha genes, whereas the gene encoding the 77,357-molecular-weight polypeptide increased this activity. Insertion of the stop codons abolished these activities.


The association between distress tolerance and eating expectancies among trauma-exposed college students with obesity.
Objective Obesity is a significant health concern among college populations, and trauma-exposed students are particularly at risk for behaviors associated with weight gain. There is need for further understanding of factors that may contribute to increased obesity among this population. Participants: Participants included 139 trauma-exposed college students with obesity (76.3% females; Mage = 25.4 years, SD = 8.07). Method: The current cross-sectional study examined distress tolerance in terms of expectancies of eating to help manage negative affect and to lead to feeling out of control among trauma-exposed college students with obesity. Results: Results indicated that lower perceived distress tolerance was associated with greater expectancies of eating to help manage negative affect and to lead to feeling out of control. Conclusions: These findings suggest that distress tolerance may be a clinically significant target for treatment in order to better understand and treat expectancies of eating among trauma-exposed college students with obesity.


Comparison of direct immunofluorescence and ELISA for the detection of Chlamydia trachomatis antigen in the patients of pelvic inflammatory disease.
Fifty female patients clinically diagnosed as pelvic inflammatory disease (PID) attending Gynaecology OPD of Smt. Sucheta Kriplani Hospital were studied for the presence of Chlamydial antigen by direct immunofluorescence (DFA) and Enzyme linked immunosorbant assay (ELISA) test. Out of fifty PID patients Chlamydia tracchomatis lipopolysaccharide antigen could be detected in 28% of cases by ELISA and Chlamydial outer membrane protein antigen could be detected in 32% of cases by DFA. Although in the present study DFA and ELISA compare well with each other, but DFA has been found to be more specific test as it detects outer membrane protein antigen of Chlamydia trachomatis.


Transforming health and well-being through publishing computable biomedical knowledge (CBK).
Computable biomedical knowledge artifacts (CBKs) are software programs that transform input data into practical output. CBKs are expected to play a critical role in the future of learning health systems. While there has been rapid growth in the development of CBKs, broad adoption is hampered by limited verification, documentation, and dissemination channels. To address these issues, the Learning Health Systems journal created a track dedicated to publishing CBKs through a peer-review process. Peer review of CBKs should improve reproducibility, reuse, trust, and recognition in biomedical fields, contributing to learning health systems. This special issue introduces the CBK track with four manuscripts reporting a functioning CBK, and another four manuscripts tackling methodological, policy, deployment, and platform issues related to fostering a healthy ecosystem for CBKs. It is our hope that the potential of CBKs exemplified and highlighted by these quality publications will encourage scientists within learning health systems and related biomedical fields to engage with this new form of scientific discourse.


Problems with essential fatty acids: time for a new paradigm?
The term 'essential fatty acid' is ambiguous and inappropriately inclusive or exclusive of many polyunsaturated fatty acids. When applied most rigidly to linoleate and alpha-linolenate, this term excludes the now well accepted but conditional dietary need for two long chain polyunsaturates (arachidonate and docosahexaenoate) during infancy. In addition, because of the concomitant absence of dietary alpha-linolenate, essential fatty acid deficiency is a seriously flawed model that has probably led to significantly overestimating linoleate requirements. Linoleate and alpha-linolenate are more rapidly beta-oxidized and less easily replaced in tissue lipids than the common 'non-essential' fatty acids (palmitate, stearate, oleate). Carbon from linoleate and alpha-linolenate is recycled into palmitate and cholesterol in amounts frequently exceeding that used to make long chain polyunsaturates. These observations represent several problems with the concept of 'essential fatty acid', a term that connotes a more protected and important fatty acid than those which can be made endogenously. The metabolism of essential and non-essential fatty acids is clearly much more interconnected than previously understood. Replacing the term 'essential fatty acid' by existing but less biased terminology, i.e. polyunsaturates, omega3 or omega6 polyunsaturates, or naming the individual fatty acid(s) in question, would improve clarity and would potentially promote broader exploration of the functional and health attributes of polyunsaturated fatty acids.


Fetal hemoglobin: optimum conditions for its estimation by alkali denaturation.
Alkali denaturation is the most commonly used technic to estimate fetal hemoglobin in red blood cells. The Betke and colleagues method (Nature 184: 1959; 1877-78) using cyanmethemoglobin (HiCN) was recommended by an International Committee for Standardization in Hematology for fetal hemoglobin levels between 2 and 40%. We showed that precision with samples containing up to 5% fetal hemoglobin can be considerably improved by measuring the absorbance of HiCN at 420 nm rather than at 540 nm because the molar absorptivity is 10 times greater in the Soret band. To determine optimum conditions for the assay, we studied the kinetics and stoichiometry of conversion of hemoglobin to HiCN with various concentrations and mixtures of ferricyanide, kinetics of alkali denaturation, ammonium sulfate precipitation of denatured HiCN, filtration as opposed to centrifugation for separating denatured HiCN, stability of HiCn in water and KCN solutions, and linearity of absorbance in the Soret band. With our modified procedure, the CV with normal amounts (less than 1%) of fetal hemoglobin improved from 28% to 8.7%. The CVs with 6.8% and 55% fetal hemoglobin were 7.0-4.4% respectively, and linear estimates were obtained with cells containing up to 50% fetal hemoglobin. We conclude that our modified alkali denaturation procedure yields reliable and reproducible estimates of fetal hemoglobin over a wide range of concentrations.


Intrapulpal Temperature Rise During Light Activation of Restorative Composites in a Primary Molar.
To investigate intrapulpal temperature rise in a primary molar during light activation of a composite restoration to determine if clinically significant pulpal temperatures (greater than 5.5 degrees Celsius) were reached. Restorative composites (EsthetX HD, Filtek Supreme Ultra, Filtek Bulk Fill) were placed into a primary molar with occlusal preparation (1.5 mm depth; remaining pulpal floor thickness one mm). The pulp was extirpated through a root access to place a thermocouple against the pulpal roof. Temperature changes were recorded during composite restoration light polymerization with three curing lights (one quartz-tungsten-halogen, two LEDs). Sample size was 10. Samples received additional irradiation to assure complete polymerization, followed by a third irradiation for calculating the exothermic heat contribution (subtracting third irradiation temperatures from first irradiation temperatures). Cured restorations were removed after each test, and the tooth was reused. Results were analyzed with Kruskal-Wallis (α =0.05). Type of curing light and composite material affected the intrapulpal temperature rise, which was up to five degrees Celsius for one combination of LED-composite. Clinicians should be aware of the potential for clinically significant intrapulpal temperature rises when light-activating composite restorations in a primary molar with a moderately deep cavity.


Genetic basis and timing of a major mating system shift in Capsella.
A crucial step in the transition from outcrossing to self-fertilization is the loss of genetic self-incompatibility (SI). In the Brassicaceae, SI involves the interaction of female and male specificity components, encoded by the genes SRK and SCR at the self-incompatibility locus (S-locus). Theory predicts that S-linked mutations, and especially dominant mutations in SCR, are likely to contribute to loss of SI. However, few studies have investigated the contribution of dominant mutations to loss of SI in wild plant species. Here, we investigate the genetic basis of loss of SI in the self-fertilizing crucifer species Capsella orientalis, by combining genetic mapping, long-read sequencing of complete S-haplotypes, gene expression analyses and controlled crosses. We show that loss of SI in C. orientalis occurred < 2.6 Mya and maps as a dominant trait to the S-locus. We identify a fixed frameshift deletion in the male specificity gene SCR and confirm loss of male SI specificity. We further identify an S-linked small RNA that is predicted to cause dominance of self-compatibility. Our results agree with predictions on the contribution of dominant S-linked mutations to loss of SI, and thus provide new insights into the molecular basis of mating system transitions.


Second-order nonlinearity induced transparency.
In analogy to electromagnetically induced transparency, optomechanically induced transparency was proposed recently in [Science330, 1520 (2010)SCIEAS0036-807510.1126/science.1195596]. In this Letter, we demonstrate another form of induced transparency enabled by second-order nonlinearity. A practical application of the second-order nonlinearity induced transparency is to measure the second-order nonlinear coefficient. Our scheme might find applications in quantum optics and quantum information processing.


Mode-Specific Vibrational Analysis of Exciton Delocalization and Structural Dynamics in Conjugated Oligomers.
Exciton delocalization in organic semiconducting polymers, affected by structures at a molecular level, plays a crucial role in modulating relaxation pathways, such as charge generation and singlet fission, which can boost device efficiency. However, the structural diversity of polymers and broad signals from typical electronic spectroscopy have their limits when it comes to revealing the interplay between local structures and exciton delocalization. To tackle these problems, we apply femtosecond stimulated Raman spectroscopy in archetypical conjugated oligothiophenes with different chain lengths. We observed Raman frequency dispersions of symmetric bond stretching modes and mode-specific kinetics in the S1 Raman spectra, which underpins the subtle and complex interplay between exciton delocalization and bond length alternation along the conjugation coordinate. Our results provide a more general picture of exciton delocalization in the context of molecular structures for conjugated materials.


Plasma and urinary levels of vasopressin in enuretic and non-enuretic children.
Plasma and urinary levels of vasopressin were measured by radioimmunoassay in 18 children with primary nocturnal enuresis and 20 age and sex matched controls. All subjects followed a protocol whereby all urine were collected and divided up into daytime (8 a.m.-8 pm) and night-time (8 p.m. - 8 a.m.) samples. Urine osmolality and urinary vasopressin levels were measured and, following an overnight observation period, the following morning (8 a.m.) plasma vasopressin was measured. Plasma vasopressin was significantly lower in the enuretic group (2.86 +/- 0.44 pg/ml) compared to the control group (3.64 +/- 1.35 pg/ml) (p = 0.011). Total urinary vasopressin excretion over 24 hours was lower in the enuretic group but the difference was not significant. These results support the hypothesis that one of the factors responsible for nocturnal enuresis in children may be due to a reduced nocturnal secretion of vasopressin. This may explain why the vasopressin substitution therapy is able to successfully abolish nocturnal enuresis symptoms.


Temporal changes in tissue repair upon repeated exposure to thioacetamide.
In an earlier study it was reported that a single low dose of thioacetamide (TA, 50 mg/kg) administered 36 h prior to challenge with a high dose of 400 mg/kg offers protection from lethality of high dose (Mangipudy et al., Pharmacol. Toxicol. 77, 1995). The mechanism underlying this protection was found to be preplaced hepatocellular division and tissue repair that peaked by 36 h following the low-dose treatment. In a separate study using the dose-response paradigm, it was established that the rate and the extent of the tissue repair response following infliction of injury after acute exposure has a critical bearing on the ultimate outcome of toxicity (Mangipudy et al., Environ. Health Perspect. 103, 1995). The objective of this study was to investigate the cell proliferation dynamics after repeated exposure to TA (50 mg/kg i.p.). Male Sprague-Dawley rats (200-225 g) were administered TA at intervals of 96 h. Liver injury and tissue repair were studied over a time course following each treatment. Tissue repair was estimated by S-phase DNA synthesis measuring 3H-thymidine incorporation into hepatonuclear DNA while liver injury was estimated by serum alanine aminotransferase activity. After the first dose of 50 mg/kg, peak S-phase DNA synthesis was observed at 36 h. This returned to control values by 96 h at which time the rats are known to overcome liver injury. A second dose of TA (repeated dose 1, RD1) resulted in peak S-phase DNA synthesis 12 h later at 48 h. Following the third dose (RD2) a dramatic increase in S-phase DNA synthesis was noted from as early as 12 h. Much higher peak was observed at 72 h. Interestingly, following the fourth dose (RD3) S-phase stimulation did not occur. Instead, a significant latency was observed for cells in the S-phase DNA synthesis even at time points as late as 144 h following the treatment. Liver injury on the other hand exhibited no significant differences between repetitions until RD2. However, injury was sustained in the rats treated with the fourth dose (RD3) while it returned to control levels in the earlier three instances. Sustained prolongation of liver injury after the fourth dose is presumably because tissue repair was not operational. Thus repeated exposure to TA causes a significant increase in tissue repair response although it is temporally delayed until a threshold is reached. Repetition beyond the threshold results in a marked attenuation of the repair response. These findings suggest that toxicodynamics of cell proliferation are altered after repeated exposure.


Action of a minimal contractile bactericidal nanomachine.
R-type bacteriocins are minimal contractile nanomachines that hold promise as precision antibiotics1-4. Each bactericidal complex uses a collar to bridge a hollow tube with a contractile sheath loaded in a metastable state by a baseplate scaffold1,2. Fine-tuning of such nucleic acid-free protein machines for precision medicine calls for an atomic description of the entire complex and contraction mechanism, which is not available from baseplate structures of the (DNA-containing) T4 bacteriophage5. Here we report the atomic model of the complete R2 pyocin in its pre-contraction and post-contraction states, each containing 384 subunits of 11 unique atomic models of 10 gene products. Comparison of these structures suggests the following sequence of events during pyocin contraction: tail fibres trigger lateral dissociation of baseplate triplexes; the dissociation then initiates a cascade of events leading to sheath contraction; and this contraction converts chemical energy into mechanical force to drive the iron-tipped tube across the bacterial cell surface, killing the bacterium.


A study to evaluate mobility of teeth during menstrual cycle using Periotest.
Over a century, an increased prevalence of gingival disease associated with increasing plasma sex steroid hormone levels has been reported. These situations present unique challenges to the oral health care professional. It is believed that hormonal fluctuations such as those associated with pregnancy, menstruation, and use of hormonal contraceptives lead to an increase in tooth mobility. However, this effect of female sex hormones on periodontal ligament and tooth supporting alveolar bone has rarely been investigated. So this study was undertaken to understand the effect on tooth mobility because of hormonal changes during the menstrual cycle. The mobility of index teeth 16, 13, 21, 23, 24, 36, 33, 41, 43, and 44 was measured with Periotest in 50 females at menstruation, ovulation, and premenstruation time points. Simplified oral hygiene index, plaque index, gingival index, and probing depth were also evaluated during the different phases of menstrual cycle for each subject participating in the study. The results of the study were subjected to statistical analysis. Data analysis was done by applying Z test for comparing difference between two sample means. The stages of menstrual cycle had no significant influence on the Periotest value. Despite no significant change in plaque levels, GI was significantly higher during ovulation and premenstruation time points. No change in tooth mobility was seen during the phases of the menstrual cycle. However, an exaggerated gingival response was seen during ovulation and premenstruation time when the entire menstrual cycle was observed.


Synthesis and pharmacological evaluation in mice of new non-classical antinociceptive agents, 5-(4-arylpiperazin-1-yl)-4-benzyl-1,2-oxazin-6-ones.
Several 5-(4-arylpiperazin-1-yl)-4-benzyl-1,2-oxazin-6-ones have been synthesized and tested for analgesic activity in a visceral pain model (phenylbenzoquinone-induced writhing test = PBQ test). A good correlation has been found between the antinociceptive effects of drugs and both their lipophilic and steric properties. The most active derivatives 5c and 5f, with intraperitoneal ED50 values of 10.5 and 10.3 mg kg-1 respectively, were more extensively investigated by evaluating their analgesic activity in a somatosensory pain model (hot plate test), as well as their sedative properties. Furthermore, naloxone suppressed the effect of 5c and 5f in the PBQ test, though these derivatives were ineffective to potentiate morphine analgesia. Pretreatment with yohimbine did not significantly attenuate the analgesic effects of 5c and 5f. In addition, pretreatment with 5-hydroxytryptophan associated with carbidopa also failed to potentiate the antinociceptive effects of 5c and 5f. So, a part of the analgesic activity of 5c and 5f seems to be related to an opioidergic mechanisms, especially at the mu receptor level. Molecular modeling studies performed on the opiate drug morphine and on the most stable conformer of 5f showed structural similarities between these two molecules.


Sonographic evaluation of anterior cervical lymph nodes.
In this study we evaluated the role of ultrasound in diagnosis of anterior cervical lymph (ACL) node disease. Three-hundred and sixty-six patients were included in the study. When ACL nodes were found, we noted the station(s) involved, the number, and the short and long axis of each. Patients had their thyroid investigated and were then divided into four groups: no sonographic signs of thyroid abnormality, already diagnosed autoimmune thyroiditis, probable new diagnosis of autoimmune thyroiditis, and thyroid nodules. ACL nodes were found in 127 out of 366 patients examined. The 127 patients with ACL nodes were classified into group 1 (2 patients), group 2 (97 patients), group 3 (23 patients), and group 4 (5 patients). The only differences were the presence and number of lymph nodes in the prelaryngeal and/or prethyroidal and/or pretracheal stations, and the number of "acutely inflamed" nodes in group 3 compared with all the other groups. We observed a strong association between anterior cervical lymphadenopathy and autoimmune thyroiditis; this is certainly a good reason to justify thorough evaluation of anterior cervical lymph nodes for all patients with suspected thyroiditis.


Symptom self-management strategies reported by adolescents and young adults with cancer receiving chemotherapy.
Adolescents and young adults (AYAs) with cancer experience multiple symptoms related to their cancer and its treatment which can negatively impact their development and quality of life. An understanding of the strategies AYAs use to self-manage their symptoms is limited. This study described symptom self-management strategies reported by AYAs with cancer using an iPad-based symptom heuristics tool, the Computerized Symptom Capture Tool. The study used a cross-sectional, descriptive design. AYAs' free text responses relating their symptom self-management strategies were explored using qualitative content analysis procedures. Strategies were examined overall and by individual symptoms. Seventy-two AYAs 13-29 years of age (mean 18.4 years) reported a total of 772 symptom self-management codes for 585 individual symptoms. These codes were organized into 119 distinct categories. These categories were further organized into 16 subthemes and 3 overarching themes: "Things I Take … or Not" (n = 209 codes), "Physical Care Things I Do" (n = 367 codes), and "Psychosocial Care Things I Do" (n = 132 codes). AYAs frequently reported strategies from all three of the symptom self-management themes to manage individual symptoms; however, "medications" was the most frequently reported strategy. AYAs receiving chemotherapy use multiple common, yet uniquely individual symptom self-management strategies. AYAs' reported strategies range from those that involve shared management with a healthcare provider to those that AYAs implement independently. The study provides a foundation for future research to empower AYAs to engage in symptom self-management and to guide healthcare providers as they discuss developmentally relevant and evidence-based symptom self-management strategies.


The Spectrum of CYP21A2 Gene Mutations from 16 Families of Congenital Adrenal Hyperplasia: Genotype-Phenotype Correlation.
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder of the adrenal steroidogenic pathway. The most common form of CAH is due to 21-hydroxylase deficiency resulting from mutations in CYP21A2 gene. The present study aimed to identify CYP21A2 common gene mutations, phenotype correlation, and to analyze the segregation pattern in CAH patients, parents, and siblings. Sixteen families having at least one classic CAH child in each family, a total of 58 subjects were recruited. The presence of six most common gene mutations, namely, Intron 2 (c.293-13A/C>G), c.844G>T (p.Val282Leu), c.1019G>A (p.Arg340His), c.92C>T (p.Pro31Leu), c.955C>T (p.Gln319*), and c.518T>A (p.Ile173Asn) in CYP21A2 gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using specific primers. Out of 16 classic CAH females analyzed, salt-wasting (SW) form was present in 12 (75%) and simple virilizing form in four (25%) children. Isolated clitoromegaly was the most common clinical presentation followed by ambiguous genitalia. The most common mutation observed in CAH patient population was Intron 2 (c.293-13A/C>G) (100%) followed by p.Pro31Leu (98%), p.Gln319* (93%), p.Val282Leu (91.4%), and p.Ile173Asn (19%). Although p.Arg340His mutation was not observed in this study. Interestingly, Intron 2 (c.293-13A/C>G) homozygous was observed in 31.3% of the entire study cohort and p.Ile173Asn mutation was found to be associated with SW form. Our results suggested a high prevalence of CYP21A2 gene mutations among CAH patients and heterogeneous mutation spectrum in their families of south Indian cohort. The outcomes afford valuable evidence for premarital and prenatal screening as well as planning suitable programs to prevent the development of CAH in Indian population.


Computational Architecture of the Parieto-Frontal Network Underlying Cognitive-Motor Control in Monkeys.
The statistical structure of intrinsic parietal and parieto-frontal connectivity in monkeys was studied through hierarchical cluster analysis. Based on their inputs, parietal and frontal areas were grouped into different clusters, including a variable number of areas that in most instances occupied contiguous architectonic fields. Connectivity tended to be stronger locally: that is, within areas of the same cluster. Distant frontal and parietal areas were targeted through connections that in most instances were reciprocal and often of different strength. These connections linked parietal and frontal clusters formed by areas sharing basic functional properties. This led to five different medio-laterally oriented pillar domains spanning the entire extent of the parieto-frontal system, in the posterior parietal, anterior parietal, cingulate, frontal, and prefrontal cortex. Different information processing streams could be identified thanks to inter-domain connectivity. These streams encode fast hand reaching and its control, complex visuomotor action spaces, hand grasping, action/intention recognition, oculomotor intention and visual attention, behavioral goals and strategies, and reward and decision value outcome. Most of these streams converge on the cingulate domain, the main hub of the system. All of them are embedded within a larger eye-hand coordination network, from which they can be selectively set in motion by task demands.


[Computerized retrospective study of 141 children operated on for vesico-ureteral reflux].
Follow-up study of 141 cases of vesico-ureteric reflux (less than 10 years old) treated by Cohen's method. Computerized study, 5 years after treatment, with analysis of the influence of different parameters (type of VUR, age, sex, urinary infection or not, space of time between diagnosis and treatment) on the renal parenchymal radiographic measurements ( Hodson 's method). The youngest is the child when he is treated, the best is the functional result.


Biofilm formation on zirconia and titanium over time-An in vivo model study.
The aim of this study was to evaluate volume, vitality and diversity of biofilms on the abutment materials zirconia and titanium as a function of time using an in vivo model for the biofilm formation. The development of biofilms on zirconia and titanium grade 4 test specimens in the human oral cavity over time was analysed. After pretreatment, a total of 96 titanium and 96 zirconia discs were fixed on 12 composite splints, which were worn by 12 volunteers. After 6 hr, 24 hr, 3 days and 5 days, biofilms on 48 specimens of each material were analysed with confocal laser scanning microscopy (CLSM). The microbiota composition on the other 48 test specimens was examined using full-length 16S sequence analysis. Statistical analysis was performed by SPSS and R, and level of significance was set at 0.05. Confocal laser scanning microscopy analysis of the biofilms revealed significant changes in volume over time on zirconia and titanium. The material did not significantly influence the volume or live/dead ratio at the individual time points. The composition of the microbiome was influenced by the age of the biofilm, but not by the material of the test specimen. The most frequently found bacteria were Streptococcus spp., followed by Neisseria spp., Rothia spp., Haemophilus spp., Gemella spp. and Abiotrophia spp. On both materials, the quantity and diversity of the microbiome increased over time. Apart from a slight difference in Veillonella abundance at one time point, there were no significant differences between zirconia and titanium.


Transient hyperthyroxinemia in newborns from women with autoimmune thyroid disease and raised levels of thyroid peroxidase antibodies.
Although it is well established that maternal thyroid disease and increased levels of thyrotropin receptor antibodies (TRab) during pregnancy are associated with a number of complications, is the significance of increased levels of thyroid peroxidase antibodies (TPOab) alone a matter for discussion? The aim of the present study was to examine whether transplacental passage of TPOab from women with autoimmune thyroid disease (AITD) interferes with thyroid function in the neonate. Pregnant women with AITD (raised levels of TPOab) and their neonates were monitored with regard to variations of thyroid hormones, thyrotropin (TSH), and TPOab. Pregnant women with non-AITD served as controls. The neonates from mothers with AITD, independently of the presence also of TRab in the mothers, had a transient hyperthyroxinemia one week following birth. Neonatal TPOab correlated with that of the mothers at gestation and was cleared concomitantly with normalization of thyroxine. A high frequency (21%) of severe hyperbilirubinemia was observed in neonates from mothers with AITD. Children of mothers with raised levels of TPOab, have a transient hyperthyroxinemia one week after birth accompanied by a high frequency of hyperbilirubinemia suggesting that clinical examination and blood testing should be performed consecutively during the first postnatal week.


2-(2-Iodo-phen-yl)isoindoline-1,3-dione.
In the title compound, C(14)H(8)INO(2), the dihedral angle between the isoindole ring and the phenyl ring of the 1-iodo-benzene group is 84.77 (15)°. There is a short inter-molecular I⋯O contact of 3.068 (3) Å in the crystal.


Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial.
Physicians may use either insulin or exenatide injections for patients with type 2 diabetes mellitus who have poor glycemic control despite taking oral blood glucose-lowering drugs. To compare effects of exenatide and insulin glargine on glycemic control in patients with type 2 diabetes mellitus that is suboptimally controlled with metformin and a sulfonylurea. 26-week multicenter, open-label, randomized, controlled trial. 82 outpatient study centers in 13 countries. 551 patients with type 2 diabetes and inadequate glycemic control (defined as hemoglobin A1c level ranging from 7.0% to 10.0%) despite combination metformin and sulfonylurea therapy. Exenatide, 10 microg twice daily, or insulin glargine, 1 daily dose titrated to maintain fasting blood glucose levels of less than 5.6 mmol/L (<100 mg/dL). Hemoglobin A1c level, fasting plasma glucose level, body weight, 7-point self-monitored blood glucose, standardized test-meal challenge, safety, and tolerability. Baseline mean hemoglobin A1c level was 8.2% for patients receiving exenatide and 8.3% for those receiving insulin glargine. At week 26, both exenatide and insulin glargine reduced hemoglobin A1c levels by 1.11% (difference, 0.017 percentage point [95% CI, -0.123 to 0.157 percentage point]). Exenatide reduced postprandial glucose excursions more than insulin glargine, while insulin glargine reduced fasting glucose concentrations more than exenatide. Body weight decreased 2.3 kg with exenatide and increased 1.8 kg with insulin glargine (difference, -4.1 kg [CI, -4.6 to -3.5 kg]). Rates of symptomatic hypoglycemia were similar, but nocturnal hypoglycemia occurred less frequently with exenatide (0.9 event/patient-year versus 2.4 events/patient-year; difference, -1.6 events/patient-year [CI, -2.3 to -0.9 event/patient year]). Gastrointestinal symptoms were more common in the exenatide group than in the insulin glargine group, including nausea (57.1% vs. 8.6%), vomiting (17.4% vs. 3.7%) and diarrhea (8.5% vs. 3.0%). The trial was open-label and did not assess clinical complications related to diabetes. Of the 551 participants, 19.4% of those receiving exenatide and 9.7% of those receiving insulin glargine withdrew from the study. Only 21.6% of the insulin glargine group and 8.6% of the exenatide group achieved the target level for fasting plasma glucose of less than 5.6 mmol/L (<100 mg/dL). Exenatide and insulin glargine achieved similar improvements in overall glycemic control in patients with type 2 diabetes that was suboptimally controlled with oral combination therapy. Exenatide was associated with weight reduction and had a higher incidence of gastrointestinal adverse effects than insulin glargine.


Approaching value in asthma management: the need to integrate clinical and economic research with the basic science.
In the management of asthma, clinical decision making is primarily directed toward achieving the best outcome for the patient. However, the interests of the provider, insurer, and employer must also be taken into account. Integral to this process is an understanding of the need to weigh therapeutic objectives against economic concerns. This process involves consideration of the potential for clinical benefit as opposed to adverse treatment effects, as well as direct and indirect costs. Data from clinical trials provide the foundation for evaluating these factors. Randomized clinical trials, postmarketing studies, surveillance programs, and observational claims analyses all contribute valuable information to facilitate this process. Taken together, the results of such analyses form a foundation for providing effective, safe, and cost-efficient care through the practice of evidence-based medicine.


Interferon alpha for treatment of chronic myeloid leukemia.
Treatment of chronic myeloid leukemia (CML) with interferon-alpha (IFN-α) was introduced in the early 1980s. Several clinical trials showed a survival advantage for patients treated with IFN-α compared to conventional chemotherapy. Some patients achieved longstanding complete cytogenetic remissions (i.e. >2 log tumor mass reduction). IFN-α was then recommended as first line medical treatment until 2001. The mechanism of this anti-leukemic effect is not clear, although IFN-α has many effects of potential relevance on stem cells and immunology. There is no evidence of benefit for high dose (in practice a maximally tolerated dose) compared with lower dose IFN-α. When IFN-α is combined with other drugs, we advice lower dose IFN to minimize toxicity and increase treatment adherence and duration. IFN-α combined with Ara-C moderately improves treatment outcome. Imatinib, a tyrosine kinase inhibitor, is now first line treatment for CML, but two large randomized studies show improved outcome when pegylated IFN-α is added to the treatment with imatinib. One explanation for this might be that IFN-α, contrary to imatinib, stimulates the quiescent stem cells to proliferate and thereby potentially increases sensitivity to imatinib. Although imatinib and other tyrosine kinase inhibitors are very efficient, they are rarely curative. IFN-α could be included in curatively aimed combination treatment protocols and thus still be an important element in CML treatment.


Controlled Electrostatic Self-Assembly of Ibuprofen-Cationic Dextran Nanoconjugates Prepared by low Energy Green Process - a Novel Delivery Tool for Poorly Soluble Drugs.
The direct effect of electrostatic interaction between ibuprofen and cationic dextran on the system-specific physicochemical parameters and intrinsic dissolution characteristics of ibuprofen was evaluated in order to develop drug-polymer nanoconjugate as a delivery strategy for poorly soluble drugs. Amorphous ibuprofen-DEAE dextran (Ddex) nanoconjugate was prepared using a low energy, controlled amphiphile-polyelectrolyte electrostatic self-assembly technique optimized by ibuprofen critical solubility and Ddex charge screening. Physicochemical characteristics of the nanoconjugates were evaluated using FTIR, DSC, TGA, NMR and SEM relative to pure ibuprofen. The in vitro release profiles and mechanism of ibuprofen release were determined using mathematical models including zero and first order kinetics; Higuchi; Hixson-Crowell and Korsmeyer-Peppas. Electrostatic interaction between ibuprofen and Ddex was confirmed with FT-IR, (1)H NMR and (13)C NMR spectroscopy. The broad and diffused DSC peaks of the nanoconjugate as well as the disappearance of ibuprofen melting peak provided evidence for their highly amorphous state. Low concentrations of Ddex up to 1.0 × 10(-6) g/dm(3) enhanced dissolution of ibuprofen to a maximum of 81.32% beyond which retardation occurred steadily. Multiple release mechanisms including diffusion; discrete drug dissolution; anomalous transport and super case II transport were noted. Controlled assembly of ibuprofen and Ddex produced a novel formulation with potential extended drug release dictated by Ddex concentration.


Fowlpoxvirus recombinants coding for the CIITA gene increase the expression of endogenous MHC-II and Fowlpox Gag/Pro and Env SIV transgenes.
A complete eradication of an HIV infection has never been achieved by vaccination and the search for new immunogens that can induce long-lasting protective responses is ongoing. Avipoxvirus recombinants are host-restricted for replication to avian species and they do not have the undesired side effects induced by vaccinia recombinants. In particular, Fowlpox (FP) recombinants can express transgenes over long periods and can induce protective immunity in mammals, mainly due to CD4-dependent CD8+ T cells. In this context, the class II transactivator (CIITA) has a pivotal role in triggering the adaptive immune response through induction of the expression of class-II major histocompatibility complex molecule (MHC-II), that can present antigens to CD4+ T helper cells. Here, we report on construction of novel FPgp and FPenv recombinants that express the highly immunogenic SIV Gag-pro and Env structural antigens. Several FP-based recombinants, with single or dual genes, were also developed that express CIITA, driven from H6 or SP promoters. These recombinants were used to infect CEF and Vero cells in vitro and determine transgene expression, which was evaluated by real-time PCR and Western blotting. Subcellular localisation of the different proteins was evaluated by confocal microscopy, whereas HLA-DR or MHC-II expression was measured by flow cytometry. Fowlpox recombinants were also used to infect syngeneic T/SA tumour cells, then injected into Balb/c mice to elicit MHC-II immune response and define the presentation of the SIV transgene products in the presence or absence of FPCIITA. Antibodies to Env were measured by ELISA. Our data show that the H6 promoter was more efficient than SP to drive CIITA expression and that CIITA can enhance the levels of the gag/pro and env gene products only when infection is performed by FP single recombinants. Also, CIITA expression is higher when carried by FP single recombinants than when combined with FPgp or FPenv constructs and can induce HLA-DR cell surface expression. However, in-vivo experiments did not show any significant increase in the humoral response. As CIITA already proved to elicit immunogenicity by improving antigen presentation, further in-vivo experiments should be performed to increase the immune responses. The use of prime/boost immunisation protocols and the oral administration route of the recombinants may enhance the immunogenicity of Env peptides presented by MHC-II and provide CD4+ T-cell stimulation.


A bountiful harvest: genomic insights into crop domestication phenotypes.
Human selection during crop domestication has resulted in remarkable transformations of plant phenotypes, providing a window into the genetic basis of morphological evolution. Recent progress in our understanding of the genetic architecture of novel plant traits has emerged from combining advanced molecular technologies with improved experimental designs, including nested association mapping, genome-wide association studies, population genetic screens for signatures of selection, and candidate gene approaches. These studies reveal a diversity of underlying causative mutations affecting phenotypes important in plant domestication and crop improvement, including coding sequence substitutions, presence/absence and copy number variation, transposon activation leading to novel gene structures and expression patterns, diversification following gene duplication, and polyploidy leading to altered combinatorial capabilities. The genomic regions unknowingly targeted by human selection include both structural and regulatory genes, often with results that propagate through the transcriptome as well as to other levels in the biosynthetic and morphogenetic networks.


AdipoRon and ADP355, adiponectin receptor agonists, in Metabolic-associated Fatty Liver Disease (MAFLD) and Nonalcoholic Steatohepatitis (NASH): A systematic review.
Adiponectin replacement therapy holds the potential to benefit numerous human diseases, and ongoing research applies particular interest in how adiponectin acts against Metabolic-associated Fatty Liver Disease (MAFLD) and Nonalcoholic Steatohepatitis (NASH). However, the pharmacological limitations of the intact protein have prompted a focus on alternative options, specifically peptidic and small molecule agonists targeting the adiponectin receptor. AdipoRon is an extensively researched non-peptidic drug candidate in adiponectin replacement therapy. In turn, ADP355 is an adiponectin-based active short peptide. They have garnered significant attention due to their potential as substitutes for adiponectin. Researchers have studied AdipoRon's and ADP355's efficacy and therapeutic applications in various disease conditions. However, the effects of AdipoRon and ADP355 against NAFLD and NASH models advanced more, and no systematic review explored this area before. This systematic review was conceived to address the deficiency mentioned above and consider the lack of clinical evidence. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were utilized. To assess the risk of bias in systematic review, The Joanna Briggs Institute (JBI) Critical Appraisal Checklist was employed. Results from pre-clinical evidence show that AdipoRon and ADP355 represent promising effects in NAFLD and NASH-related models, including reducing hepatic steatosis, modulating inflammation, improving insulin sensitivity, enhancing mitochondrial function, and protecting against liver fibrosis. While AdipoRon and ADP355 exhibit promise in pre-clinical studies and experimental models, additional clinical trials are necessary to assess their effectiveness, safety, and potential translational therapeutic potential uses in NAFLD and NASH human cases.


Emergence and Spread of kelch13 Mutations Associated with Artemisinin Resistance in Plasmodium falciparum Parasites in 12 Thai Provinces from 2007 to 2016.
Artemisinin-based combination therapy (ACT) is the most effective and widely used treatment for uncomplicated Plasmodium falciparum malaria and is a cornerstone for malaria control and prevention globally. Resistance to artemisinin derivatives has been confirmed in the Greater Mekong Subregion (GMS) and manifests as slow parasite clearance in patients and reduced ring stage susceptibility to artemisinins in survival assays. The P. falciparumkelch13 gene mutations associated with artemisinin-resistant parasites are now widespread in the GMS. We genotyped 277 samples collected during an observational study from 2012 to 2016 from eight provinces in Thailand to identify P. falciparum kelch13 mutations. The results were combined with previously reported genotyping results from Thailand to construct a map illustrating the evolution of P. falciparum kelch13 mutations from 2007 to 2016 in that country. Different mutant alleles were found in strains with different geographical origins. The artemisinin resistance-conferring Y493H and R539T mutations were detected mainly in eastern Thailand (bordering Cambodia), while P574L was found only in western Thailand and R561H only in northwestern Thailand. The C580Y mutation was found across the entire country and was nearing fixation along the Thai-Cambodia border. Overall, the prevalence of artemisinin resistance mutations increased over the last 10 years across Thailand, especially along the Thai-Cambodia border. Molecular surveillance and therapeutic efficacy monitoring should be intensified in the region to further assess the extent and spread of artemisinin resistance.


[The Perruce decree, an opportunity to question the acceptance of a handicap and the relationship between physicians, justice and society].
The 'Perruche' decree (confirmed by the Paris Court of Cassation in November 2001) recognizes the right of those born with a handicap to claim for compensation. However, there is a fear that this decree might lead to deviations in the requests submitted for systematic compensation, simply because of a handicap or prejudice, even in the absence of a medical error. The interest of the 'Perruche' decree is that it once again raises the question of the management of handicapped people in our society and the lack of sufficient help from the State. The decree also emphasizes the strong subjacent risk that a handicap could be considered as a failure or a medical error. The excessive ideology of a 'perfect' child may therefore provoke the reject of the idea that a human being may be born with a deficiency or "imperfection". It also reminds us that medical practice remains exposed to errors and incertitude and that a zero risk does not exist, contrary to certain fantastical beliefs fostered by the principle of precaution. The hazard may correspond to the notion of incertitude. But it must not be confused with an error and it implies that which is unforeseeable. It is important that physicians stall the faith in the power of ultramodern techniques. Conversely, they should not claim a right to systematic error, when errors in fact hide authentic faults. The medical discourse must therefore remain responsible.


Nitrification utilizing CaCO3 as the buffering agent.
Nitrification utilizing chalk (calcium carbonate) as the buffering agent was investigated. Three different fluidized bed reactor configurations were examined in order to study the effect of reactor layout on nitrification and concomitant chalk dissolution. The first system consisted of two interconnected columns with high recycle rate, one containing zeolite as the carrier for the nitrifying biomass and the other chalk as the buffering agent. The second reactor system consisted of a single column containing both zeolite and chalk particles. In the third system, nitrification was carried out in a single column where chalk particles were used both as the carrier for the biomass and as the buffer. Results showed that only the reactor with chalk acting as both the buffering agent and the biomass carrier could be operated without external buffer (NaHCO3) addition. This system operated at high ammonium removal rates of up to 2.5 g N l(-1) reactor d(-1) even though the bulk solution of the reactor had a low pH of 5.5. The high nitrification efficiency at this low pH was probably mainly a result of a favorable microenvironment surrounding the nitrifying biomass attached to the chalk.


Deep sequencing analysis of transcriptomes in Aspergillus flavus in response to resveratrol.
Resveratrol has been reported as a natural phytoalexin that inhibits infection or the growth of certain fungi including Aspergillus flavus. Our previous research revealed that aflatoxin production in A. flavus was reduced in medium with resveratrol. To understand the molecular mechanism of the A. flavus response to resveratrol treatment, the high-throughput paired-end RNA-Seq was applied to analyze the transcriptomic profiles of A. flavus. In total, 366 and 87 genes of A. flavus were significantly up- and down- regulated, respectively, when the fungus was treated with resveratrol. Gene Ontology (GO) functional enrichment analysis revealed that 48 significantly differentially expressed genes were involved in 6 different terms. Most genes in the aflatoxin biosynthetic pathway genes cluster (#54) did not show a significant change when A. flavus was treated with resveratrol, but 23 of the 30 genes in the #54 cluster were down-regulated. The transcription of aflA and aflB was significantly suppressed under resveratrol treatment, resulting in an insufficient amount of the starter unit hexanoate for aflatoxin biosynthesis. In addition, resveratrol significantly increased the activity of antioxidative enzymes that destroy radicals, leading to decreased aflatoxin production. Moreover, stuA, fluG, flbC, and others genes involved in mycelial and conidial development were down-regulated, which disrupted the cell's orderly differentiation and blocked conidia formation and mycelia development. The transcripts of laeA and veA were slightly inhibited by resveratrol, which may partly decrease aflatoxin production and depress conidia formation. Resveratrol can affect the expression of A. flavus genes that are related to developmental and secondary metabolic processes, resulting in decreased aflatoxin production and conidia formation and could also cause abnormal mycelia development. These results provide insight into the transcriptome of A. flavus in response to resveratrol and a new clew for further study in regulation of aflatoxin biosynthesis in A. flavus.


Markers in the epidermal growth factor receptor pathway and skin toxicity during erlotinib treatment.
Skin toxicity is a common adverse effect of erlotinib and other anti-epidermal growth factor receptor (EGFR) agents. The aim of the study was to explore the relationship between markers in the EGFR pathway and skin rash. Eighteen patients with metastatic breast cancer were treated with daily oral erlotinib at 150 mg. Skin biopsies were obtained at baseline and after 1 month of treatment in 15 patients. EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated Akt (pAkt) or Ki67 were examined quantitatively by immunohistochemistry. 11 of 18 (61%, 95% confidence interval 35.7% to 82.7%) patients developed skin rash. pAkt at baseline was significantly higher in patients with no rash than those with a grade 1 or 2 rash (18.8 +/- 8.3 versus 2.4 +/- 1.2 versus 3.3 +/- 3.3; P = 0.0017 for trend). There was a trend towards a significant increase of pMAPK in skin posttreatment with increasing grade of rash (no rash versus grade 1 versus grade 2 rash: 4.5 +/- 2.3 versus 8.4 +/- 4.2 versus 19.4 +/- 4.6; P = 0.036). Other markers were not associated with rash. pAkt was significantly associated with not developing a rash and may have a predictive utility for skin toxicity in patients treated with erlotinib and possibly with other anti-EGFR agents.


Angular dispersion compensation for ultra-broadband pulses by using a cascaded prism and hollow-core fiber configuration.
In this paper, we report that the angular dispersion of the output pulses in a nonlinear process can be efficiently compensated by using a cascaded prism(s) and short hollow-core fiber (HCF) configuration. Here, the prism(s) is used to suppress the angular dispersion and transform it into spatial chirp, while the HCF is used for removing this spatial chirp and the residual angular dispersion, which can also significantly improve the beam quality. The feasibility of this novel method is numerically and experimentally investigated with the ultra-broadband idler pulses centered at 1250 nm wavelength and generated by an LBO crystal based non-collinear optical parametric amplifier. The proof-of-principle experiment shows that the angular dispersion can be effectively removed and ultra-broadband idler pulses with good spectral quality and spatial profile can be obtained. The total transmission efficiency in the experiment is around 67% and the measured M x2 and M y2 can reach 1.12 and 1.04, respectively. To the best of our knowledge, this is the first reported ultra-broadband angular dispersion compensation scheme combining prism(s) and HCF, which can remarkably eliminate the angular dispersion while simultaneously possesses high efficiency, good spectral and beam spatial quality.


[A Recurrent Case of Thymic Adenocarcinoma Effectively Treated with S-1 Over a Long-Term Period].
A 61-year-old woman with an abnormal radiograph shadow in her anterior mediastinum was admitted to our hospital and underwent an extended thymectomy. The pathological diagnosis of the tumor was a non-papillary adenocarcinoma of the thymus in pathological stage IV b using the Masaoka classification owing to mediastinal lymph node metastasis. We found parasternal lymph node metastases 5 months after her first operation, and subsequently, she underwent surgery and adjuvant radiotherapy. We found systemic lymph node metastases and metastatic lesions in distant organs, including her lungs, brain, and kidney 27 months after her first operation. Systemic chemotherapy, such as carboplatin plus paclitaxel and an ADOC regimen were not very effective, so we performed immunohistochemical staining of the primary thymic adenocarcinoma. The levels of both thymidylate synthase and dihydropyrimidine dehydrogenase were low; therefore, we started S-1 100mg/body (2 weeks of administration, 1 week of withdrawal)31 months after her first operation. She entered complete remission 6 months after the initiation of S-1. We surgically resected her solitary lung metastasis 13 months after initiation of S-1, and then continued the S-1 treatment. There was no recurrence for more than 2 years after the lung surgery. We believe that when the expression levels of thymidylate synthase or dihydropyrimidine dehydrogenase are low in cases of recurrent thymic adenocarcinoma, S-1 may be able to induce an effective response.


Pulmonary extramedullary haematopoiesis.
A 72-year-old Caucasian lady with myeloproliferative disorder was admitted for evaluation of progressive dyspnoea, weight loss, fatigue and mild hypoxia. A diffuse ground glass opacity was seen on CT pulmonary angiogram. Differential diagnoses included heart failure, infection, progression of myeloproliferative disorder with extramedullary haematopoiesis, thromboembolism or hydroxyurea-induced lung injury. Bronchoscopy and broncho-alveolar lavage were uninformative however lung biopsy with video-assisted thoracoscopy revealed extramedullary haematopoiesis within lung parenchyma. This is a very rare complication of myeloproliferative disorder and the authors discuss the significance of the case, review the literature and report the patient's progress.


Tunable optical angular selectivity in hyperbolic metamaterial via photonic topological transitions.
An ultra-narrow angular optical transparency window based on photonic topological transition (PTT) is theoretically and numerically investigated in a low-loss hyperbolic metamaterial (HMM) platform, which consists of aligned metallic nanowires embedded indielectric host matrices. Our results indicate that, near the transition point of PTT, the designed system exhibits high-efficiency optical angular selectivity close to normal incidence by tailoring the topology of metamaterial's equi-frequency surface (EFS). Moreover, the operating wavelength (λ0) is flexibly tunable by selecting appropriate material and geometrical parameters, which provides significant guidance for the later experimental design. Our method is further applied to super-resolution imaging, with a resolution of at least λ0/4 and over a significant distances (>12λ0). The HMM-supported angularly selective system could find promising applications for high-efficiency light manipulation and lensless on-chip imaging.


Micro RNAs are involved in activation of epicardium during zebrafish heart regeneration.
Zebrafish could be an interesting translational model to understand and improve the post-infarction trial and possible regeneration in humans. The adult zebrafish is able to regenerate efficiently after resecting nearly 20% of the ventricular apex. This process requires the concert activation of the epicardium and endocardium, as well as trans-differentiation of pre-existing cardiomyocytes that together replace the lost tissue. The molecular mechanisms involved in this activation process are not completely clarified. In this work, in order to investigate if the downregulation of these miRNAs (miRs) are linked with the activation of epicardium, the expressions of miR-133a, b and miR-1 during regeneration were analysed. qPCR analyses in whole-heart, or from distinct dissected epicardial cells comparing to regenerative clot (containing cardiomyocytes, fibroblasts and endocardial cells) by a laser-micro-dissector, have indicated that already at 24 h there is a downregulation of miRs: (1) miR-133a and miR-1 in the epicardium and (2) miR-133b and miR-1 in the regenerative clot. All the miRs remain downregulated until 7 days post-surgery. With the aim to visualize the activations of heart component in combination with miRs, we developed immunohistochemistry using antibodies directed against common markers in mammals as well as zebrafish: Wilms tumour 1 (WT1), a marker of epicardium; heat-shock protein 70 (HSP70), a chaperon activated during regeneration; and the Cardiac Troponin T (cTnT), a marker of differentiated cardiomyocytes. All these markers are directly or indirectly linked to the investigated miRs. WT1 and HSP70 strongly marked the regeneration site just at 2-3 days postventricular resection. In coherence, cTnT intensively marked the regenerative portion from 7 days onwards. miRs-1 and -133 (a,b) have been strongly involved in the activation of epicardium and regenerative clot during the regeneration process in zebrafish. This study can be a useful translational model to understand the early epicardial activation in which miRs-133a and miR-1 seem to play a central role as observed in the human heart.


Neuroendocrine tumor of the gallbladder with spectral CT.
Neuroendocrine tumors (NETs) are neoplasms that arise from neural crest argyrophil cells, and often occur to the elderly, female and patients with cholelithiasis. In this case, the female patient was 38 years old and admitted into the hospital for interrupted right upward abdominal pain for 2 years plus aggravated with nausea and anorexia for 1 week. Ultrasound showed gallbladder space-occupying lesions and spectral computed tomography (CT) suggested of retroperitoneal lymph node metastasis. The patient was diagnosed with gallbladder neuroendocrine carcinoma after the surgery.


Pros and cons of specialised care in bipolar disorder: an international perspective.
Highly specialised care may have both pros and cons. Centralised expert treatment may be more effective than standard community care for bipolar disorder. Rather than trying to solve the false dichotomy between specialised v. community care, the rational integration of both approaches may enhance quality of care and cost-effectiveness.


Where similarity beats redundancy: the importance of context, higher order similarity, and response assignment.
People are especially efficient in processing certain visual stimuli such as human faces or good configurations. It has been suggested that topology and geometry play important roles in configural perception. Visual search is one area in which configurality seems to matter. When either of 2 target features leads to a correct response and the sequence includes trials in which either or both targets are present, the result is a redundant-target paradigm. It is common for such experiments to find faster performance with the double target than with either alone, something that is difficult to explain with ordinary serial models. This redundant-targets study uses figures that can be dissimilar in their topology and geometry and manipulates the stimulus set and the stimulus?response assignments. The authors found that the combination of higher order similarity (e.g., topological) among the features in the stimulus set and response assignment can effectively overpower or facilitate the redundant-target effect, depending on the exact nature of the former characteristics. Several reasonable models of redundant-targets performance are falsified. Parallel models with the potential for channel interactions are supported by the data.


[Isolated and transient hyperphosphatasemia in young children].
This report concerns a transient and isolated hyperphosphatasemia in a 33 month-old infant. Such a case is asymptomatic and benign. There is an important increase in enzymatic activity which includes both fractions (bone and liver). Pathophysiology is still unclear. This biological data is worth being known in order to avoid useless and always normal investigations.


[A case of latex allergy induced by indwelt Foley catheter].
A 7-year-old boy with microtia was scheduled for otoplasty under general anesthesia. A Foley catheter was indwelt very gently following tracheal intubation but his foreskin showed remarkable edema about 15 minutes later. All vital signs were normal. His lungs were ventilated easily and no rash or edema was found except for penis. Operation was completed uneventfully as planned. He recovered from anesthesia smoothly but foreskin edema still remained. Allergic reaction was suspected and scratch test was performed to determine the allergen on the next day. Positive reaction to Foley catheter extracts and high serum latex-specific IgE antibody level proved that latex containing Foley catheter had caused foreskin edema. All anesthesiologists should pay attention to latex allergy and interview all patients in detail in preanesthetic evaluation.


Developing and implementing collaborative nursing education research in the South.
The project, Nursing Research Development in the South, was designed to facilitate collaborative research in nursing education in the South. Funded by the Department of Health, Education, and Welfare as a three-year project of the Southern Regional Education Board and the Council on Collegiate Education for Nursing, it began in 1977. In the first year, nursing educators and clinicians identified research problems and priorities. Nurse faculty were then invited to conduct studies examining problems in the chosen areas; 78 participated in 19 collaborative research groups.


Intratumoural inflammation and endocrine resistance in breast cancer.
It is becoming clear that inflammation-associated mechanisms can affect progression of breast cancer and modulate responses to treatment. Estrogen receptor alpha (ERα (ESR1)) is the principal biomarker and therapeutic target for endocrine therapies in breast cancer. Over 70% of patients are ESR1-positive at diagnosis and are candidates for endocrine therapy. However, ESR1-positive tumours can become resistant to endocrine therapy. Multiple mechanisms of endocrine resistance have been proposed, including suppression of ESR1. This review discusses the relationship between intratumoural inflammation and endocrine resistance with a particular focus on inflammation-mediated suppression of ESR1.


Preoperative Examination and Intraoperative Identification of Hepatocellular Carcinoma Using a Targeted Bimodal Imaging Probe.
In clinical imaging modalities, MRI is suitable for preoperative examination. Fluorescence imaging has been proposed to improve the detectability of cancer lesions during the operation. However, the specificity and accuracy of the two imaging modalities is limited. To improve the prognosis and survival rate of the patient suffering from hepatocellular carcinoma (HCC), it is very important to develop a specific probe to achieve early detection and precise resection of HCC. We selected HCC targeting peptide SP94 to conjugate with a NIR dye and Gd chelated DOTA to enhance the specificity of different imaging modalities. MRI and fluorescence imaging were used for preoperative examination of the cancer and detecting the tumor in the operation, respectively. MRI and fluorescence signals significantly increased when HCC occurs and the obtained probe shows high uptake in HCC but negligible uptake in the normal liver tissues. The signal-to-background ratio is higher than 2.23 (MRI) and 2.0 (fluorescence imaging) with noninvasive imaging modalities. After the intraperitoneal cavity was surgically exposed, the signal-to-background ratio is higher than 4.6. By combining the high specificity of our probe with the high sensitivity of fluorescence imaging, the microprimary malignancy and micrometastasis foci (diameter <1 mm) can be easily detected after the intraperitoneal cavity is exposed. These results indicated that our probe is conductive to the early detection and precise resection of the HCC and has the potential to improve the diagnosis and treatment of patients with HCC.


The Ever-Evolving Concept of the Gene: The Use of RNA/Protein Experimental Techniques to Understand Genome Functions.
The completion of the human genome sequence together with advances in sequencing technologies have shifted the paradigm of the genome, as composed of discrete and hereditable coding entities, and have shown the abundance of functional noncoding DNA. This part of the genome, previously dismissed as "junk" DNA, increases proportionally with organismal complexity and contributes to gene regulation beyond the boundaries of known protein-coding genes. Different classes of functionally relevant nonprotein-coding RNAs are transcribed from noncoding DNA sequences. Among them are the long noncoding RNAs (lncRNAs), which are thought to participate in the basal regulation of protein-coding genes at both transcriptional and post-transcriptional levels. Although knowledge of this field is still limited, the ability of lncRNAs to localize in different cellular compartments, to fold into specific secondary structures and to interact with different molecules (RNA or proteins) endows them with multiple regulatory mechanisms. It is becoming evident that lncRNAs may play a crucial role in most biological processes such as the control of development, differentiation and cell growth. This review places the evolution of the concept of the gene in its historical context, from Darwin's hypothetical mechanism of heredity to the post-genomic era. We discuss how the original idea of protein-coding genes as unique determinants of phenotypic traits has been reconsidered in light of the existence of noncoding RNAs. We summarize the technological developments which have been made in the genome-wide identification and study of lncRNAs and emphasize the methodologies that have aided our understanding of the complexity of lncRNA-protein interactions in recent years.


Cystic fibrosis in a child with situs inversus, a distinctively unusual association.
Cystic fibrosis is the most frequently witnessed potentially lethal autosomal recessive, genetic disease but its incidence is extremely low in South-Asian population. We report a case Cystic Fibrosis in a patient with Situs inversus, a condition not witnessed in medical literature of Pakistan or more captivatingly even Asia. The patient was a three and half years old male child presenting with a history of fever, cough and jaundice. Physical examination lead to the initial diagnosis of situs inversus, which was confirmed by the chest radiograph, echocardiography and ultrasound of abdomen. Further evaluations were conducted to establish the cause of respiratory symptoms. The findings of pansinusitis as evidenced by the radiography and an exceedingly high sweat chloride concentration of 100 mmol/L resulted in the conclusive diagnosis of Cystic Fibrosis.


Monitoring marine recreational water quality using multiple microbial indicators in an urban tropical environment.
The microbial water quality at two beaches, Hobie Beach and Crandon Beach, in Miami-Dade County, Florida, USA was measured using multiple microbial indicators for the purpose of evaluating correlations between microbes and for identifying possible sources of contamination. The indicator microbes chosen for this study (enterococci, Escherichia coli, fecal coliform, total coliform and C. perfringens) were evaluated through three different sampling efforts. These efforts included daily measurements at four locations during a wet season month and a dry season month, spatially intensive water sampling during low- and high-tide periods, and a sand sampling effort. Results indicated that concentrations did not vary in a consistent fashion between one indicator microbe and another. Daily water quality frequently exceeded guideline levels at Hobie Beach for all indicator microbes except for fecal coliform, which never exceeded the guideline. Except for total coliform, the concentrations of microbes did not change significantly between seasons in spite of the fact that the physical-chemical parameters (rainfall, temperature, pH, and salinity) changed significantly between the two monitoring periods. Spatially intense water sampling showed that the concentrations of microbes were significantly different with distance from the shoreline. The highest concentrations were observed at shoreline points and decreased at offshore points. Furthermore, the highest concentrations of indicator microbe concentrations were observed at high tide, when the wash zone area of the beach was submerged. Beach sands within the wash zone tested positive for all indicator microbes, thereby suggesting that this zone may serve as the source of indicator microbes. Ultimate sources of indicator microbes to this zone may include humans, animals, and possibly the survival and regrowth of indicator microbes due to the unique environmental conditions found within this zone. Overall, the results of this study indicated that the concentrations of indicator microbes do not necessarily correlate with one another. Exceedence of water quality guidelines, and thus the frequency of beach advisories, depends upon which indicator microbe is chosen.


[The effect of astragalus polysaccharides (APS) on cell mediated immunity (CMI) in burned mice].
In this paper, the changes in CMI in mice were determined after burn injury, and the effects of APS on CMI of burned mice were investigated in vivo. The results showed that on day 6 postburn, spleen index and thymus index were reduced, T lymphocyte transformation and interleukin 2 (IL-2) production were suppressed. Furthermore, the serum and macrophages from burned mice showed significant suppressive activity upon T lymphocyte transformation in vitro, and suppressive index (SI) of suppressor T cell (Ts) was greater than that of normal controls. Intraperitoneal administration of APS (250mg/kg daily, from day 0 to 5 could restore spleen index and thymus index of burned mice, reverse the suppression of T lymphocyte transformation and IL-2 production, reduce remarkably the suppressive activity of serum, macrophages and Ts. It is suggested that (1) burn injury-induced suppression of CMI may be related to the augmented suppressive activity of serum, macrophages and Ts; (2) administration of APS may restore the impaired CMI after burn injury by reducing the suppressive activity of postburn serum, macrophages and Ts.


Serum levels of IGFBP7 are elevated during acute exacerbation in COPD patients.
The purpose of this study was to explore the insulin-like growth factor binding protein 7 (IGFBP7) level in the serum of chronic obstructive pulmonary disease (COPD) patients during acute exacerbation (AE). The study population consisted of 47 AECOPD patients, including 25 patients enrolled between January 2011 and February 2011 (the first group) and 22 patients enrolled from December 2011 to August 2012 (the second group) and 29 healthy controls. Chemiluminescence-linked immunoassay was used to detect serum IGFBP7 levels. For the second group patients, IGFBP7 and C-reactive protein (CRP) levels were measured both on the admission day and on the discharge day. Among the first group AECOPD patients, serum IGFBP7 levels were significantly elevated in AECOPD patients in the intensive care unit (ICU; 52.92±16.32 ng/mL), and in hospitalized AECOPD patients not in ICU (40.66±13.9), compared to healthy subjects (30.3±7.09 ng/mL; P<0.01). For the second group AECOPD patients, the increased IGFBP7 levels reduced after the patients had recovered (34.42±11.88 vs 27.24±7.2 ng/mL; P<0.01). During AE, the correlation coefficient between IGFBP7 and CRP was 0.357. In receiver operating characteristic analysis, the area under the curve was 0.799 for CRP, and 0.663 for IGFBP7 in distinguishing patients with AECOPD on the admission day from the discharge day. Serum IGFBP7 levels were raised during AECOPD. Similar to the expression pattern of CRP, the IGFBP7 levels reduced after convalescence, suggesting that IGFBP7 might have a candidate role as a biomarker of AECOPD. No significant linear correlation was detected between IGFBP7 and CRP, indicating the probable different role for the two molecules in assessing AECOPD. Further study is needed to explore the value of IGFBP7 in differentiating phenotypes of AECOPD.