[Role of the hypophysis and hypothalamus in the control of feedback of the hypophyseal-adrenocortical system].
The role of hypophysis and paraventricular hypothalamic nucleus in inhibition of pituitary-adrenocortical system induced with hydrocortisone in increasing doses (100, 300, 1200 mg/100 g b. w.) was studied in rats. The ACTH secretion induced with pituitrin was only decreased after administration of 1200 mg/100 g b. w. of hydrocortisone, whereas smaller doses did not alter the responsiveness of hypophysis. After lesion of the paraventricular hypothalamic nucleus the inhibition of the stress-induced reaction of pituitary-adrenocortical system was either eliminated or decreased depending on the dose of hydrocortisone administered. The inhibition induced with hydrocortisone in physiological doses seems to depend on the hypothalamus. However, both the hypothalamus and the hypophysis take part in an inhibition induced with supraphysiological doses of the hormone.


Diet and large intestinal disease in dogs and cats.
Large intestinal disease, and more especially colitis, is a commonly seen problem in small animal practice. Although colitis is most frequently diagnosed in dogs, it is becoming increasing common in cats. The etiology of colitis is not known, but there is general agreement that an immune-mediated response to luminal antigen is involved. In particular, parasites, bacteria and dietary factors may be involved. In approximately 10% of dogs presented with typical signs of colitis, no pathologic lesion will be found on investigation. These dogs have a functional diarrhea associated with some stress factor and are thought to have irritable bowel syndrome (IBS). This condition is most frequently observed in working dogs, although highly nervous and excitable dogs may also exhibit similar clinical signs. Until the underlying etiology of colitis is determined, treatment regimens will remain symptomatic. Recent studies have placed considerable importance on the value of diet in the prevention, immediate and long-term therapy of colitis in dogs and cats. In particular the value of "novel" protein diets, fermentable fiber and polyunsaturated fatty acids is receiving the most attention. It is now possible to maintain patients in long-term remission and to modify the severity and chronicity of colitis by using diet alone. This paper will review the subject of dietary management of colitis and IBS and present results from the author's clinical research program.


Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker on oxidative stress and metabolism of elements in kidney of STZ-induced diabetic rats.
In diabetes, increased oxidative stress and impaired trace element metabolism play an important role in the pathogenesis of diabetic nephropathy. The objective of this research was to examine the outcomes of blocking the renin-angiotensin system, using either the angiotensin-converting enzyme inhibitor (ACEI), perindopril, or the angiotensin II type 1 (AT1) receptor blocker, irbesartan, on oxidative stress and trace element levels such as Zn, Mg, Cu, and Fe in the kidneys of diabetic rats that had been induced with streptozotocin. Thirty-two Wistar albino male rats were equally divided into four groups. The first group was used as a control. The second group of rats developed diabetes after receiving a single intraperitoneal dose of STZ. The third and fourth groups of rats had STZ-induced diabetes and received daily dosages of irbesartan (15 mg/kg b.w/day) and perindopril (6 mg/kg b.w/day) treatment, respectively. Biochemical analysis of the kidneys showed a distinct increase in oxidative stress, indicated by heightened levels of malondialdehyde (MDA) and decreased superoxide dismutase (SOD) activities, as well as reduced glutathione (GSH) levels in the kidneys of diabetic rats. In the kidneys of diabetic rats, the mean levels of Fe and Cu were found to be significantly higher than those of the control group. Additionally, the mean levels of Zn and Mg were significantly lower in the diabetic rats compared to the control rats. Both perindopril and irbesartan decreased significantly MDA content and increased SOD activities and GSH levels in the kidneys of rats with diabetes. The Zn and Mg concentrations in the kidneys of diabetic rats treated with perindopril and irbesartan were markedly higher than in untreated STZ-diabetic rats, while the Cu and Fe concentrations were significantly lower. The urinary excretion of rats treated with perindopril and irbesartan showed a pronounced increase in Cu levels, along with a significant reduction in Zn and Mg levels. Although diabetic rats demonstrated degenerative morphological alterations in their kidneys, both therapies also improved diabetes-induced histopathological modifications in the kidneys. Finally, the present results suggest that manipulating the levels of Zn, Mg, Cu, and Fe - either through ACE inhibition or by blocking AT1 receptors - could be advantageous in reducing lipid peroxidation and increasing antioxidant concentration in the kidneys of diabetic rats.


Lifetime co-morbidity of panic attacks and major depression in a population-based study: age of onset.
We used survival analysis to test for a suspected effect of co-morbidity of DIS/DSM-III major depression and panic attack on the age of onset of each of these disorders, in a population-based sample from four sites of the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area Program (N = 12668). The possible effects of gender and presence of a co-morbid disorder on age of onset of the single disorders were analysed using the Cox proportion-hazard-model, with gender as an explanatory variable and the co-morbid disorders as time-dependent covariates. The disorders begin earlier in life when they are co-morbid than when they occur singly. The occurrence of one disorder increases the chance of occurrence of the other. Females have from 1.7 to almost twice the risk for developing panic and/or depression compared with men, even if the co-morbid disorder precedes the index disorder or is lifetime co-morbid. These findings are compatible with a hypothesis of a higher severity in co-morbid cases when compared with a single disorder.


Normal standard curve for acoustic pharyngometry.
Pharyngeal size, compliance, and the dynamic behavior of the upper airway are important factors in the production of obstructive sleep apnea. Assessment of the upper airway for possible site(s) of obstruction is one of the keys to a successful management of the condition. Acoustic pharyngometry has the potential for localizing such sites, however, standardizing the operating technique and producing a standard normal curve is a prerequisite before exploring the potential of this equipment. A total number of 350 normal volunteers (271 males and 79 females) were examined by acoustic pharyngometry and a coefficient of variance of 5% to 7% was obtained from each of them. Mean and standard deviation of pharyngeal area at each point of X-axis (distance) was obtained and analyzed statistically to produce a general standard curve. Using special techniques during examination, the oropharyngeal junction and glottis were located, and thus a mapped acoustic pharyngogram was produced. Mean pharyngeal area was 3.194 cm(2) in males (SD 0.311) and 2.814 cm(2) in females (SD 0.331). Mean glottic area was 1.06 cm(2) in males (SD 0.119) and 0.936 cm(2) in females (SD 0.108). A minimal pharyngeal area is probably needed as a "golden standard" to evaluate patients with obstructive sleep apnea.


Utility of heparin-binding protein following cardiothoracic surgery using cardiopulmonary bypass.
Cardiothoracic surgery using cardiopulmonary bypass (CPB) triggers an inflammatory state that may be difficult to differentiate from infection. Heparin-binding protein (HBP) is a candidate biomarker for sepsis. As data indicates that HBP normalizes rapidly after cardiothoracic surgery, it may be a suitable early marker of postoperative infection. We therefore aimed to investigate which variables influence postoperative HBP levels and whether elevated HBP concentration is associated with poor surgical outcome. This exploratory, prospective, observational study enrolled 1475 patients undergoing cardiothoracic surgery using CPB, where HBP was measured at ICU arrival. Patients with HBP in the highest tercile were compared to remaining patients. Multivariable logistic regressions were performed to identify factors predictive of elevated HBP and 30-day mortality. Overall median HBP was 30.0 ng/mL. Patients undergoing isolated CABG or surgery with CPB-duration ≤ 60 min had a median HBP of 24.9 ng/mL and 23.2 ng/mL, respectively. Independent predictors of elevated postoperative HBP included increased EuroSCORE, prolonged CPB-duration and high intraoperative temperature. Increased HBP was an independent predictor of 30-day mortality. This study confirms the promising characteristics of HBP as a biomarker for identification of postoperative sepsis, especially after routine procedures. Further studies are required to investigate whether HBP may detect postoperative infections.


Apical Periodontitis - Is It Accountable for Cardiovascular Diseases?
The aim of this review was to assess the relationship between apical periodontitis and cardiovascular diseases and the predictive factors regarding this association. Cross sectional and observational studies have been included, which are mostly retrospective. A comprehensive search was performed in the Systematic Electronic Databases, PUBMED and MEDLINE from 1919 till September 2014. Articles were also hand searched. From 86 studies identified, all were read and 58 articles which were relevant were included in the text. Some articles were excluded because they were pertaining to periodontology and other systemic disorders. Some were solely animal studies and were thus excluded. Our results suggest an independent association between cardiovascular diseases and apical periodontitis. A causal relationship could not be established since weak parameters of risk have been assessed in the studies, population taken is difficult to compare and other confounding factors have not been ruled out. Only a more focused and better instituted scientific research can determine this association. Establishing a cause and effect relationship between apical periodontitis and cardiovascular diseases can affect the course of treatment of cardiovascular diseases. It is not only of interest from the scientific point of view but also from public health perspective.


Expected gain and status number following restricted individual and combined-index selection.
Imposition of restrictions on number of individuals selected from a family and number of families from which superior individuals are selected could markedly alter the consequences of individual and combined-index selection. Predicted genetic gain and diversity measured as status number following selection were studied to draw general conclusions. Selection and its prediction were applied to two sets of real-life data. Theoretical prediction gave results close to those from factual selection. Gain and status number varied with initial family number and size, sib type, heritability, selection proportion, restriction type and intensity, and selection criteria. Proper restriction on the number of individuals selected can control the reduction of status number to an acceptable level, particularly when breeding values are used as the selection criterion. Restriction on the number of families selected would effectively improve the gain efficiency of selection based on phenotypic values. Choosing combinations of both restrictions might produce higher gain without the loss of status number. Given constant population size, family number should be large enough to ensure that restricted selection will yield higher gain and status number.


High relative fat-free mass is important for maintaining serum albumin levels in patients with compensated liver cirrhosis.
In patients with liver cirrhosis, hypoalbuminemia causes edema and ascites, and a reduction in the quality of life. Since musculature is catabolized to supply amino acids for albumin synthesis in malnutritional cirrhotic patients, muscular volume is hypothesized to play an important role in albumin production. Therefore, we investigated the correlation between serum albumin levels and the fat-free mass (FFM) in cirrhotic patients. Fifty-seven patients (26 males and 31 females) with compensated liver cirrhosis were evaluated. Patients with edema or ascites were excluded from the study. Healthy volunteers (n = 104; 48 males and 56 females) were also evaluated as controls. FFM was measured using 5-500 kHz multifrequency bioelectric impedance analysis. To minimize the difference in FFM distribution between males and females, we introduced a new marker, relative FFM (rFFM), which represents the ratio of FFM in a patient relative to that in a volunteer of the same height. Following FFM measurement, the serum albumin levels of patients were assayed monthly. In patients with active cirrhosis (alanine aminotransaminase (ALT) > 50 U/L), both albumin (the difference between maximum and minimum levels) and the standard deviation of albumin levels (SD-albumin) during the observation period showed a significant correlation with rFFM. Multiple linear regression analysis using variables such as rFFM, platelet number, and serum cholesterol levels, choline esterase, albumin, bilirubin, and ALT revealed that rFFM and ALT were significant and independent factors that influenced albumin or SD-albumin in cirrhotic patients. Our results indicate that cirrhotic patients with high rFFM showed less of a decrease in albumin levels, and that the muscle volume is one of the most important factors for maintaining serum albumins level in active cirrhosis. Exercise and protein-rich nutrition at the early stage of liver cirrhosis may be advisable for maintaining or increasing muscular volume.


Kinetic studies with rat-brain succinic-semialdehyde dehydrogenase.
A simple procedure is described that gives an approximately 100-fold purification of rat brain succinic-semialdehyde dehydrogenase with a high yield. The enzyme exhibits a relatively low Km value for succinic semialdehyde (2.5 microM) and is inhibited by high concentrations of that substrate in an uncompetitive manner with respect to NAD+ (Ki = 150 microM). p-Hydroxybenzaldehyde was shown to give competitive inhibition with respect to succinic semialdehyde and uncompetitive inhibition with respect to NAD+. Initial rate studies in the presence of a fixed concentration of this inhibitor allowed a more accurate estimation of the kinetic parameters for the uninhibited reaction. The results of these studies, together with analysis of the dead-end inhibition by AMP and the effects of NAD+ and 3-acetylpyridine--adenine dinucleotide as alternative acceptors in the reaction, were consistent with the enzyme-catalysed reaction obeying a compulsory-order mechanism in which NAD+ was the first substrate to bind to the enzyme and NADH was the last product to dissociate from it.


Gonadotrophins modulate cell death-related genes expression in human endometrium.
Background Gonadotrophins exert their functions by binding follicle-stimulating hormone receptor (FSHR) or luteinizing hormone and human chorionic gonadotropin receptor (LHCGR) present on endometrium. Within ovaries, FSH induces autophagy and apoptosis of granulosa cells leading to atresia of non-growing follicles, whereas hCG and LH have anti-apoptotic functions. Endometrial cells express functioning gonadotrophin receptors. The objective of this study was to analyze the effect of gonadotrophins on physiology and endometrial cells survival. Materials and methods Collected endometria were incubated for 48 or 72 h with 100 ng/mL of recombinant human FSH (rhFSH), recombinant human LH (rhLH) or highly purified hCG (HPhCG) alone or combined. Controls omitted gonadotrophins. The effect of gonadotrophins on cytochrome P450 family 11 subfamily A polypeptide 1 (CYP11A1), hypoxia inducible factor 1α (HIF1A), and cell-death-related genes expression was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Immunohistochemistry for microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B) and apoptotic protease activating factor 1 (APAF-1) was performed. Results Gonadotrophins are able to modulate the endometrial cells survival. FSH induced autophagy and apoptosis by increasing the relative expression of MAP1LC3B and FAS receptor. In FSH-treated samples, expression of apoptosis marker APAF-1 was detected and co-localized on autophagic cells. hCG and LH does not modulate the expression of cell-death-related genes while the up-regulation of pro-proliferative epiregulin gene was observed. When combined with FSH, hCG and LH prevent autophagy and apoptosis FSH-induced. Conclusions Different gonadotrophins specifically affect endometrial cells viability differently: FSH promotes autophagy and apoptosis while LH and hCG alone or combined with rhFSH does not.


Interconversion of red opsin isoforms by the cyclophilin-related chaperone protein Ran-binding protein 2.
Ran-binding protein 2 (RanBP2) (type II) is a retinal cyclophilin-related protein that binds Ran-GTPase. Type I cyclophilin is a shorter, alternatively spliced isoform of RanBP2. Recently, we showed that the Ran-binding domain 4 (RBD4)/cyclophilin (CY) supradomain of RanBP2 acts both in vitro and in vivo as a specific chaperone for bovine red/green opsin (R/G opsin). R/G opsin undergoes a stable modification of its electrophoretic mobility upon binding to RanBP2. This modification is likely due to cis-trans isomerization of one or more proline residues in the opsin protein. Here, we show that expression of human red opsin in Escherichia coli and COS cells results in the production of still a third electrophoretic variant of this protein. This variant was converted to the RBD4 binding-competent form of opsin through direct interaction with RBD4/CY, both in vivo and in vitro. We suggest that these distinct opsin species may represent kinetically or thermodynamically trapped prolyl conformers that can be interconverted by concerted action of the RBD4 and CY domains of RanBP2. We also show that the C-terminal half of RBD4 is the binding domain for bovine R/G opsin and that coexpression of human red opsin with type I cyclophilin in vivo enhances the production of functional visual pigment. These observations imply that prolyl isomerization may have importance beyond its role in protein folding, possibly as a molecular switch modulated by cyclophilin for the loading of opsin onto RanBP2 during visual pigment processing in cones.


Tricuspid regurgitant jet velocity elevation and its relationship to lung function in pediatric sickle cell disease.
Concerns about the morbidity and mortality associated with tricuspid regurgitant jet velocity (TRJV) elevation, which may indicate pulmonary hypertension (PHT), in adults with sickle cell disease (SCD) have prompted growing interest in screening the pediatric sickle cell population. The goals of our study were to estimate the prevalence of TRJV elevation and determine its relationship to pulmonary function in children and young adults with SCD at baseline. Seventy-eight subjects (10-24 years old) with SCD underwent prospective screening by Doppler echocardiogram (ECHO), complete lung function evaluation, and laboratory testing as part of standard care at steady state. Tricuspid regurgitation was quantifiable in 68/78 (87%) subjects and peak TRJV was > or =2.5 m/sec in 26/78 (33.3%) evaluated. The frequency of obstruction, restriction, or abnormal gas exchange found on lung function evaluation was not significantly different in subjects with and without TRJV elevation. However, significant inverse correlations were observed between TRJV and both % predicted forced vital capacity (FVC) (r = -0.29, P = 0.022) and oxygen saturation (r = -0.26, P = 0.036). When compared to subjects without TRJV elevation, subjects with TRJV elevation had significantly lower % predicted forced expiratory volume in 1 sec (FEV(1)) (78.9 +/- 14.4 vs. 86.6 +/- 13.0%, P = 0.023), FVC (82.8 +/- 14.1 vs. 90.7 +/- 12.9%, P = 0.017), and oxygen saturation (95.8 +/- 3.2 vs. 97.5 +/- 2.4%, P = 0.016). We found that the combination of low hemoglobin and low % predicted FVC best predicted TRJV elevation (chi(2) = 17.05, P = 0.001) in our cohort, correctly identifying 70% of cases and resulting in positive and negative predictive values of 60 and 74%, respectively. We conclude that in this young population with SCD, TRJV elevation that is not significantly associated with abnormal lung function is common at baseline.


Interactions between SRY and SOX genes in mammalian sex determination.
The SRY gene on the mammalian Y chromosome undoubtedly acts to determine testis, but it is still quite unclear how. It was originally supposed that SRY acts directly to activate other genes in the testis-determining pathway. This paper presents an alternative hypothesis that SRY functions indirectly, by interacting with related genes SOX3 (from which SRY evolved) and SOX9 (which appears to be intimately involved in vertebrate gonad differentiation). Specifically, I propose that in females SOX3 inhibits SOX9 function, but in males, SRY inhibits SOX3 and permits SOX9 to enact its testis-determining role. This hypothesis makes testable predictions of the phenotypes of XX and XY individuals with deficiencies or overproduction of any of the three genes, and is able to account for the difficult cases of XX(SRY-) males and transdifferentiation in the absence of SRY. The hypothesis also suggests a way that the dominant SRY sex-determining system of present-day mammals may have evolved from an ancient system relying on SOX3 dosage.


Integrated Myofibrillar Protein Synthesis in Recovery From Unaccustomed and Accustomed Resistance Exercise With and Without Multi-ingredient Supplementation in Overweight Older Men.
Background: We previously showed that daily consumption of a multi-ingredient nutritional supplement increased lean mass in older men, but did not enhance lean tissue gains during a high-intensity interval training (HIIT) plus resistance exercise training (RET) program. Here, we aimed to determine whether these divergent observations aligned with the myofibrillar protein synthesis (MyoPS) response to acute unaccustomed and accustomed resistance exercise. Methods: A sub-sample of our participants were randomly allocated (n = 15; age: 72 ± 7 years; BMI: 26.9 ± 3.1 kg/m2 [mean ± SD]) to ingest an experimental supplement (SUPP, n = 8: containing whey protein, creatine, vitamin D, and n-3 PUFA) or control beverage (CON, n = 7: 22 g maltodextrin) twice per day for 21 weeks. After 7 weeks of consuming the beverage alone (Phase 1: SUPP/CON only), subjects completed 12 weeks of RET (twice per week) + HIIT (once per week) (Phase 2: SUPP/CON + EX). Orally administered deuterated water was used to measure integrated rates of MyoPS over 48 h following a single session of resistance exercise pre- (unaccustomed) and post-training (accustomed). Results: Following an acute bout of accustomed resistance exercise, 0-24 h MyoPS was 30% higher than rest in the SUPP group (effect size: 0.86); however, in the CON group, 0-24 h MyoPS was 0% higher than rest (effect size: 0.04). Nonetheless, no within or between group changes in MyoPS were statistically significant. When collapsed across group, rates of MyoPS in recovery from acute unaccustomed resistance exercise were positively correlated with training-induced gains in whole body lean mass (r = 0.63, p = 0.01). Conclusion: There were no significant between-group differences in MyoPS pre- or post-training. Integrated rates of MyoPS post-acute exercise in the untrained state were positively correlated with training-induced gains in whole body lean mass. Our finding that supplementation did not alter 0-48 h MyoPS following 12 weeks of training suggests a possible adaptive response to longer-term increased protein intake and warrants further investigation. This study was registered at ClinicalTrials.gov. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02281331.


College students' relationships with siblings.
Two hundred and seventy-five college undergraduates coming from families of 2-7 children completed questionnaires about their relationships with their siblings. Aspects of intersibling communication, influence, and current and past affective relationships were investigated. The relationships reported were generally more positive than those revealed in other investigations of younger children. Presence of two parents in the home, size of the sibling group, and ordinal position of the respondent student had particular effects upon reported relationships. Furthermore, there were qualitative differences in the relationships between sibling pairs of different ordinal statuses. Results indicate that relationships between siblings have both complementary and reciprocal features, and caution against unidimensional characterizations.


Evaluation of free thyroxine methods in the presence of iodothyronine-binding autoantibodies.
Circulating iodothyronine-binding autoantibodies interfere with total T4 and T3 RIAs, giving falsely high or falsely low values depending on the assay separation method used. Direct serum free T4 (FT4) measurement should compensate for such abnormal binding if the method is free of artefact. We assessed 5 different FT4 methods in 12 patients with immunoglobulin binding of iodothyronines, with limited assessment of a sixth method in 2 subjects. Thyroid status was assessed clinically and by measurement of TSH and its response to TRH. T4 methods which use analog tracers, i.e. Amerlex, and Clinical Assays One-step FT4, gave spuriously high values in almost all hypothyroid and some euthyroid patients, due to immunoglobulin binding of the tracers used in these techniques. The kinetic indirect method (Corning Immunophase FT4) gave inappropriately high values in 4 of 6 hypothyroid patients. FT4 by equilibrium dialysis or by adsorption chromatography and RIA, accurately assessed thyroid status. These findings suggest that FT4 methods are valid in patients with circulating iodothyronine-binding immunoglobulins only if the free hormone fraction is physically separated from serum binding proteins before the assay procedure.


Does the "Morning Morality Effect" Apply to Prehospital Anaesthesiologists? An Investigation into Diurnal Changes in Ethical Behaviour.
The "morning morality effect"-the alleged phenomenon that people are more likely to act in unethical ways in the afternoon when they are tired and have less self-control than in the morning-may well be expected to influence prehospital anaesthesiologist manning mobile emergency care units (MECUs). The working conditions of these units routinely entail fatigue, hunger, sleep deprivation and other physical or emotional conditions that might make prehospital units predisposed to exhibit the "morning morality effect". We investigated whether this is in fact the case by looking at the distribution of patient transports to hospital with and without physician escort late at night at the end of the shift as a surrogate marker for changing thresholds in ethical behaviour. All missions over a period of 11 years in the MECU in Odense were reviewed. Physician-escorted transports to hospital were compared with non-physician-escorted transports during daytime, evening, and night-time (which correlates with time on the 24 h shifts). In total, 26,883 patients were transported to hospital following treatment by the MECU. Of these, 27.4% (26.9%-27.9%) were escorted to the hospital. The ratio of patient transports to hospital with and without physician escort during the three periods of the day did not differ (p = 1.00). We found no evidence of changes in admission patterns over the day. Thus, no evidence of the expected "morning morality effect" could be found in a prehospital physician-manned emergency care unit.


Automatic implantable cardioverter defibrillator. Current status.
The automatic implantable cardioverter defibrillator was conceived by Mirowski as an implantable device for detection and termination of ventricular fibrillation. Since the initial human implant of the defibrillator in 1980, there has been a dramatic expansion of the clinical experience with more than 5000 implants. The technology of the device, which is now capable of sensing and terminating both ventricular tachycardia and fibrillation, has evolved rapidly. Although still not an ideal antiarrhythmic device, it has already had a major impact on arrhythmic mortality with a marked reduction in the sudden death rates in a high-risk patient population.


Dissection of MKK6 and p38 Signaling Using Light-Activated Protein Kinases.
Stress-activated signaling pathways orchestrate cellular behaviors and fates. Studying the precise role(s) of stress-activated protein kinases is challenging, because stress conditions induce adaptation and impose selection pressure. To meet this challenge, we have applied an optogenetic system with a single plasmid to express light-activated p38α or its upstream activator, MKK6, in conjunction with live-cell fluorescence microscopy. In starved cells, decaging of constitutively active p38α or MKK6 by brief exposure to UV light elicits rapid p38-mediated signaling, release of cytochrome c from mitochondria, and apoptosis with different kinetics. In parallel, light activation of p38α also suppresses autophagosome formation, similarly to stimulation with growth factors that activate PI3K/Akt/mTORC1 signaling. Active MKK6 negatively regulates serum-induced ERK activity, which is p38-independent as previously reported. Here, we reproduce that result with the one plasmid system and show that although decaging active p38α does not reduce basal ERK activity in our cells, it can block growth factor-stimulated ERK signaling in serum-starved cells. These results clarify the roles of MKK6 and p38α in dynamic signaling programs, which act in concert to actuate apoptotic death while suppressing cell survival mechanisms.


The Staphylococcus aureus α-Acetolactate Synthase ALS Confers Resistance to Nitrosative Stress.
Staphylococcus aureus is a worldwide pathogen that colonizes the human nasal cavity and is a major cause of respiratory and cutaneous infections. In the nasal cavity, S. aureus thrives with high concentrations of nitric oxide (NO) produced by the innate immune effectors and has available for growth slow-metabolizing free hexoses, such as galactose. Here, we have used deep sequencing transcriptomic analysis (RNA-Seq) and 1H-NMR to uncover how S. aureus grown on galactose, a major carbon source present in the nasopharynx, survives the deleterious action of NO. We observed that, like on glucose, S. aureus withstands high concentrations of NO when using galactose. Data indicate that this resistance is, most likely, achieved through a distinct metabolism that relies on the increased production of amino acids, such as glutamate, threonine, and branched-chain amino acids (BCAAs). Moreover, we found that under NO stress the S. aureus α-acetolactate synthase (ALS) enzyme, which converts pyruvate into α-acetolactate, plays an important role. ALS is proposed to prevent intracellular acidification, to promote the production of BCAAs and the activation of the TCA cycle. Additionally, ALS is shown to contribute to the successful infection of murine macrophages. Furthermore, ALS contributes to the resistance of S. aureus to beta-lactam antibiotics such as methicillin and oxacillin.


[Long QT and torsade de pointes in a patient with acquired human immunodeficiency virus infection in multitherapy with drugs affecting cytochrome P450].
In acquired human immunodeficiency virus (HIV) infection, a long depolarization period at ECG may be the consequence of cardiac complications due to viral myocarditis or cardiomyopathy or indirectly due to autonomic neuropathy, or sometimes resulting from pharmacological treatments. Several drugs administered for direct treatment of HIV disease or its complications, such as antiretrovirus, fluconazole, and antibiotics, may induce ventricular arrhythmias due to long QT prolonged depolarization period. Also methadone, frequently associated with HIV therapy to treat patients with opiate addiction, is described in the literature to have cardiac inotropic effects. It has also the potential to increase the QT period and to develop ventricular torsade de pointes, primarily through interference with the rapid component of the delayed rectifier potassium ion current. Moreover, the use of methadone associated with other inhibitors of cytochrome P450 might increase plasma concentrations and contribute to methadone cardiac toxicity. We report the case of an HIV patient receiving antiretroviral treatment, fluconazole and high-dose methadone, who suddenly complained of vertigo, dizziness, pre-syncope and syncope due to severe ventricular arrhythmias that disappeared after discontinuation of all treatments.


Can we measure prior postmenopausal estrogen/progestin use? The Postmenopausal Estrogen/Progestin Interventions Trial. The PEPI Investigators.
The objective of this study was to assess: 1) the accuracy of a single self-report question about postmenopausal estrogen use; and 2) the performance and repeated measures agreement of a standardized hormone use interview. Women (n = 863) in the Postmenopausal Estrogen/Progestin Interventions Trial (PEPI) completed a self-report baseline questionnaire (BQ) at enrollment and a History of Hormone Use interview (HHU) at the 3-month follow-up visit (HHU3mos). A subsample of 101 women completed a second HHU interview 3 years later (HHU3yrs). As determined by the HHU3mos, 479 (56%) of women had ever used postmenopausal estrogen and 261 (30%) had ever used postmenopausal progestin. The mean number of years since last estrogen or progestin use was 2.2 and 1.3 years, respectively. Overall, there was 95% agreement between self-reported estrogen use on the BQ and the HHU3mos (kappa = 0.91). Using the HHU3mos as the criterion standard, the BQ misclassified 2.3% of women as false positives and 6.3% as false negatives. The average duration of estrogen use in the false-negative classifications was 1.9 years (range: 1-9 years). On the HHU3mos, 39.7% of participants could not recall at least one of the specific details of estrogen use (preparation, dose, route, or starting or stopping year); similar patterns of recall were found for progestin use. Factors associated with discordant reporting of ever-use of ERT (BQ vs. HHU3mos) or incomplete reporting of estrogen/progestin use on the HHU3mos were: route of administration, recency of hormone use, duration of hormone use, and race. Age, years since menopause, education, income, and hysterectomy status were not related to discordant and/or incomplete reporting. Agreement between the HHU3mos and HHU3yrs for ever-use of estrogen was 85.2% (kappa = 0.71). In sum, a single self-report question was adequate to ascertain ever-use of postmenopausal estrogen. When a structured interview form was used, details of postmenopausal estrogen and progestin use were not well remembered. Some features of hormone use and participant characteristics were associated with completeness of recalled hormone use, which suggests the potential for differential misclassification.


Direct gas measurements indicate that the novel cyclooxygenase inhibitor AZD3582 is an effective nitric oxide donor in vivo.
1. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donor that inhibits COX-1 and COX-2. It is as effective as naproxen in models of pain and inflammation, but causes less gastroduodenal damage. Nitric oxide (NO) is generated from AZD3582 in vitro, and this study sought to show that the drug donates NO in vivo. 2. In anaesthetised male New Zealand white rabbits, the endogenous NO concentration in exhaled air was reduced by N(G)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(- 1) i.v.) from 33.5+/-1.0 ppb (mean+/-s.e.m.; n=6 per group) to 3.0+/-1.0 ppb, while increasing blood pressure and reducing heart rate. AZD3582 (0.2, 0.6, 2.0 or 6.0 micromol kg(- 1) min(- 1)) given 30 min after L-NAME increased the concentration of NO in exhaled air (P<0.05), decreased blood pressure and increased heart rate in a dose-dependent manner versus L-NAME control values. The peak mean NO concentration obtained was 44+/-8.0 ppb. 3. In in situ-perfused rabbit lungs, L-NAME (185 micromol l(- 1)) reduced the NO concentration in exhaled air from 106+/-13 to 4.0+/-0.4 ppb (n=5). Addition of AZD3582 (6 micromol min(- 1)) to the perfusate produced an initial rapid increase in the NO concentration in exhaled air, followed by a sustained, but lower plateau. Infusion of L-NAME increased, and AZD3582 decreased, pulmonary arterial pressure. 4. In both anaesthetised rabbits and in the perfused lungs, brief periods of hypoxia increased NO concentrations generated by AZD3582. 5. We conclude that, in rabbits, AZD3582 donates NO in vivo with characteristics similar to those reported for nitroglycerin and isosorbide nitrates


Hemoptysis: etiology, evaluation, and outcome in a tertiary referral hospital.
Hemoptysis, an important and alarming symptom, often indicates serious disease. This study was designed to assess the different causes of hemoptysis, the relative importance of the different diagnostic modalities employed, and the outcome in an Israeli population cohort. A retrospective analysis of 208 patients with hemoptysis at the Hadassah University Hospital, Jerusalem, Israel between January 1980 and August 1995. Bronchiectasis (20%), lung cancer (19%), bronchitis (18%), and pneumonia (16%) accounted for most causes of hemoptysis. In contrast to older studies, active tuberculosis was a rare finding (1.4%). Bronchiectasis and bleeding diathesis were major causes of moderate to severe hemoptysis while bronchitis and lung cancer were commonly associated with milder degrees of bleeding. CT scan was the most sensitive diagnostic test when employed alone, with a positive yield of 67%. However, it failed to locate at least three cases of lung cancer. When combining a CT study together with a bronchoscopy, the positive yield increased to 93%. The mortality rate for patients with mild to moderate hemoptysis was low (2.5% and 6%, respectively), while patients with massive hemoptysis had high mortality rates (38%). Patients with lung cancer or bleeding diathesis had higher mortality rates compared with the rest of the cohort. Hemoptysis is a common symptom with a good prognosis in most cases. However, patients exhibiting massive bleeding or those with lung malignancy and patients with bleeding diathesis had a poorer prognosis. Patients older than 50 years with a positive smoking history need an extensive evaluation and follow-up to exclude lung carcinoma. The combined use of bronchoscopy and chest CT has the best yield in evaluating hemoptysis.


The role of physiology in the development of golf performance.
The attainment of consistent high performance in golf requires effective physical conditioning that is carefully designed and monitored in accordance with the on-course demands the player will encounter. Appreciating the role that physiology plays in the attainment of consistent performance, and how a player's physicality can inhibit performance progression, supports the notion that the application of physiology is fundamental for any player wishing to excel in golf. With cardiorespiratory, metabolic, hormonal, musculoskeletal and nutritional demands acting on the golfer within and between rounds, effective physical screening of a player will ensure physiological and anatomical deficiencies that may influence performance are highlighted. The application of appropriate golf-specific assessment methods will ensure that physical attributes that have a direct effect on golf performance can be measured reliably and accurately. With the physical development of golf performance being achieved through a process of conditioning with the purpose of inducing changes in structural and metabolic functions, training must focus on foundation whole-body fitness and golf-specific functional strength and flexibility activities. For long-term player improvement to be effective, comprehensive monitoring will ensure the player reaches an optimal physical state at predetermined times in the competitive season. Through continual assessment of a player's physical attributes, training effectiveness and suitability, and the associated adaptive responses, key physical factors that may impact most on performance success can be determined.


COVID-19 infection in pediatric subjects: study of 36 cases in Conakry.
The aim of this study was to evaluate the main clinical and evolutionary features of SARS-CoV-2 infection in children aged 0-18 years who were suspected and diagnosed for COVID-19 during routine consultations in the pediatric ward of the Ignace Deen National Hospital in Conakry. This retrospective study targeted all children admitted to the Pediatrics Department during the study period and focused on children whose clinical examination and/or history indicated a suspicion of SARS-CoV-2 infection. Only children with a positive reverse transcriptase-polymerase chain reaction (RT-PCR) test were included. Clinical and paraclinical data were rigorously analyzed. Anonymity and respect for ethical rules were the norm. Medical records were used as the data source and a questionnaire was developed for collection. The analysis was done using STATA/SE version 11.2 software. The mean age of the patients observed was 9.66±1.32 years, with a sex ratio of 1.25. The history of the patients found that 36.11 had already been in contact with a COVID-19 positive subject, of which 8 or 22 had close relatives treated for COVID-19 and 5 had been with classmates treated for COVID-19. Fever and physical asthenia, runny nose and throat pain were respectively found in 58.33%, 50% and 30.55% of patients with irritability in 25%. Asymptomatic children were 30.55%. The diagnosis was confirmed after a positive RT-PCR test. Thoracic computed tomography (CT) scan was normal in 80.55% of the children. They were given mostly azithromycin 15mg/kg, zinc and chloroquine sulfate 5mg/kg. The mean age of the patients observed was 9.66 years, with a sex ratio of 1.25. The history of the patients found that 36.11 had already been in contact with a COVID-19 positive subject, of which 8 or 22 had close relatives treated for COVID-19 and 5 had been with classmates treated for COVID-19. Fever and physical asthenia, runny nose and throat pain were respectively found in 58.33%, 50% and 30.55% of patients with irritability in 25%. Asymptomatic children were 30.55%. The diagnosis was confirmed after a positive RT-PCR test. Thoracic computed tomography (CT) scan was normal in 80.55% of the children. They were given mostly azithromycin 15mg/kg, zinc and chloroquine sulfate 5mg/kg.


[Tyr1]-nociceptin and nociceptin have similar naloxone-insensitive erectile activity in the cat.
The heptadecapeptide nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL1. The present study was undertaken to investigate responses to intracavernosal injections of the nociceptin analog [Tyr1]-nociceptin and to investigate the effects of naloxone on erectile responses in anesthetized cats to [Tyr1]-nociceptin and to nociceptin. Intracavernosal injections of [Tyr1]-nociceptin and of nociceptin in doses of 0.3-30 nmol elicited dose-related increases in cavernosal pressure, which, at the highest dose studied, were comparable to increases induced by the triple-drug standard (papaverine, phentolamine, and prostaglandin E1), a preparation used in the treatment of erectile dysfunction. Responses to [Tyr1]-nociceptin were rapid in onset and had a time course similar to responses to nociceptin. Metenkephalin increased cavernosal pressure, whereas injections of nociceptin-(2-17), dynorphin A, and beta-endorphin did not alter cavernosal pressure. Erectile responses to nociceptin and to [Tyr1]-nociceptin were not altered after administration of the opioid receptor antagonist naloxone at a time when erectile responses to metenkephalin were attenuated. These data show that [Tyr1]-nociceptin and nociceptin have similar naloxone-insensitive erectile activity in the cat.


RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro.
Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity.


Palisade Endings of Extraocular Muscles Develop Postnatally Following Different Time Courses.
To analyze in a frontal-eyed mammal (cat) the postnatal development of palisade endings in extraocular muscles (EOMs) and to compare the spatiotemporal and quantitative patterns of palisade endings among individual rectus muscles. Cats of different ages ranging from birth to adult stage were studied. EOM whole-mount preparations were fluorescently labeled using six combinations of triple staining and analyzed in the confocal laser scanning microscope. Palisade endings developed postnatally and passed in each rectus muscle through the same, three developmental steps but in a heterochronic sequence and to a different final density per muscle. Specifically, palisade ending development was first completed in the medial rectus and later in the inferior, lateral, and superior rectus. The highest density of palisade endings was observed in the medial rectus and the lowest in the lateral rectus whereas values for the inferior and superior rectus were in between. Palisade endings expressed high levels of growth associated protein 43 during development and were supplied by axons that established motor terminals. Cats open their eyes 7 to 10 days after birth and later develop a complex three-dimensional visuomotor climbing and jumping behavior depending on accurate binocular vision and fine tuning of the ocular movements. Our findings indicate that palisade ending development correlates with important landmarks in visuomotor behavior and provide support for our previous notion that palisade endings play an important role for convergence eye movements in frontal-eyed species.


TcNPR3 from Theobroma cacao functions as a repressor of the pathogen defense response.
Arabidopsis thaliana (Arabidopsis) NON-EXPRESSOR OF PR1 (NPR1) is a transcription coactivator that plays a central role in regulating the transcriptional response to plant pathogens. Developing flowers of homozygous npr3 mutants are dramatically more resistant to infection by the pathogenic bacterium Pseudomonas syringae, suggesting a role of NPR3 as a repressor of NPR1-mediated defense response with a novel role in flower development. We report here the characterization of a putative NPR3 gene from the tropical tree species Theobroma cacao (TcNPR3). Like in Arabidopsis, TcNPR3 was constitutively expressed across a wide range of tissue types and developmental stages but with some differences in relative levels compared to Arabidopsis. To test the function of TcNPR3, we performed transgenic complementation analysis by introducing a constitutively expressing putative TcNPR3 transgene into an Arabidopsis npr3 mutant. TcNPR3 expressing Arabidopsis plants were partially restored to the WT pathogen phenotype (immature flowers susceptible to bacterial infection). To test TcNPR3 function directly in cacao tissues, a synthetic microRNA targeting TcNPR3 mRNA was transiently expressed in cacao leaves using an Agrobacterium-infiltration method. TcNPR3 knock down leaf tissues were dramatically more resistance to infection with Phytophthora capsici in a leaf bioassay, showing smaller lesion sizes and reduced pathogen replication. We conclude that TcNPR3 functions similar to the Arabidopsis NPR3 gene in the regulation of the cacao defense response. Since TcNPR3 did not show a perfect complementation of the Arabidopsis NPR3 mutation, the possibility remains that other functions of TcNPR3 remain to be found. This novel knowledge can contribute to the breeding of resistant cacao varieties against pathogens through molecular markers based approaches or biotechnological strategies.


MSWI bottom ash used as basement at two pilot-scale roads: comparison of leachate chemistry and reactive transport modeling.
The recycling of municipal solid waste incineration bottom ash as aggregates for road basement requires assessing the long-term evolution of leachate chemistry. The Dåva (Sweden) and Hérouville (France) pilot-scale roads were monitored during 6 and 10 years, respectively. Calculated saturation indices were combined to batch test modeling to set a simplified geochemical model of the bottom ash materials. A common reactive transport model was then applied to both sites. At Hérouville, pH and the concentration of most elements quickly drop during the first two years to reach a set of minimum values over 10 years. The decrease is less pronounced at Dåva. The evolutions of pH and major element concentrations are fairly well related to the following pH-buffering sequence: portlandite, C-S-H phases or pseudo-wollastonite and, finally, calcite in equilibrium with atmospheric CO(2). Al(OH)(3), barite, ettringite and monohydrocalcite may also control leachate chemistry. Cu release is correctly modeled by DOM complexation and tenorite equilibrium. Temperature has no significant effect on the modeling of leachate chemistry in the range 5-30°C, except at high pH. Effects at road edges and roadside slopes are important for the release of the less reactive elements and, possibly, for carbonation processes.


Cancer Attributable to Asbestos Exposure in Shipbreaking Workers: A Matched-Cohort Study.
Long-term follow-up studies of asbestos-related cancer in shipbreaking workers are lacking. This study examines the relationship between cancer incidence and asbestos exposure among former Taiwan shipbreaking workers. A total of 4,427 shipbreaking workers and 22,135 population-based matched controls were successfully followed in this study. The study cohort was linked to the Taiwan Cancer Registry for new cancer cases. The adjusted hazard ratio (aHR) for cancer was calculated for the shipbreaking workers with Total Exposure Potential Scores (TEP) for asbestos. Follow-up generated 109,932 person-years, with 940 deaths and 436 cancer cases, among 4,427 shipbreaking workers from 1985 to 2008. The high asbestos exposure group also had a statistically significant increase in the risk of overall cancer (aHR= 1.71; 95% CI: 1.42-2.05), esophagus cancer (aHR= 2.31; 95% CI: 1.00-5.41), liver and intrahepatic bile duct cancer (aHR= 1.60; 95% CI: 1.08-2.36), and trachea, bronchus, and lung cancer (aHR= 3.08; 95% CI: 1.80-5.25). Mesothelioma cases were found in the high asbestos exposure group. Moreover, overall cancer, esophagus cancer, and trachea, bronchus, and lung cancer were seen in a dose-dependent relationship with asbestos exposure. This study presented the elevated trend of asbestos exposure with cancer incidence for overall cancer, esophagus cancer, and trachea, bronchus, and lung cancer among shipbreaking workers. Those workers previously exposed to asbestos should receive persistent monitoring in order to early detect adverse health outcomes.


A look into the ductoscope: its role in pathologic nipple discharge.
Mammary ductoscopy allows direct visualization of the ductal system and a method for directed excision and pathologic diagnosis. We reviewed our experience with mammary ductoscopy in the evaluation of pathologic nipple discharge. We reviewed all patients who underwent ductoscopy for pathologic nipple discharge at our institution from 2006-2010. All procedures were performed by a single surgeon. Data included patient and imaging characteristics, indications, operative findings, and pathologic outcomes. Descriptive statistics were used for data summary. During the study period, 121 patients underwent ductoscopy and directed duct excision for pathologic nipple discharge, including 66 (55%) with bloody discharge. Breast imaging [mammography, ultrasound, and/or magnetic resonance imaging (MRI)] revealed BIRADS category I/II/III findings in 112 (93%), BIRADS category IV findings in 6 (5%), and was unknown in 3 (2%) patients. Final pathology revealed papillomas in 64 (53%) patients, duct ectasia and associated benign findings in 48 (40%) patients, ductal carcinoma in situ (DCIS) in 7 (6%) patients, and atypical ductal hyperplasia in 2 (1%) patients. None of the patients with DCIS underwent preductoscopy MRI, but all had BIRADS category I/II/III breast imaging. The extent of DCIS identified by ductoscopy and subsequent surgical excision ranged from <1 cm to 10 cm (median 3 cm). The majority of patients with pathologic nipple discharge have benign nonproliferative findings or benign papillomas. Although atypia and malignancy were diagnosed in only 7% of patients who underwent ductoscopy for pathologic nipple discharge, there were no routine imaging findings indicative of these diagnoses preoperatively.


Bioturbation by a reintroduced digging mammal reduces fuel loads in an urban reserve.
Digging animals may alter many characteristics of their environment as they disrupt and modify the ground's surface by creating foraging pits or burrows. Extensive disturbance to the soil and litter layer changes litter distribution and availability, potentially altering fuel loads. In many landscapes, including peri-urban areas, fire management to reduce fuel loads is complex and challenging. The reintroduction of previously common digging animals, many of which are now threatened, may have the added benefit of reducing fuel loads. We experimentally examined how the reintroduction of a marsupial bandicoot, quenda (Isoodon fusciventer), altered surface fuel loads in an urban bush reserve in Perth, Western Australia. Foraging activities of quenda (where they dig for subterranean food) were substantial throughout the reserve, creating a visibly patchy distribution in surface litter. Further, in open plots where quenda had access, compared to fenced plots where quenda were excluded, quenda foraging significantly reduced litter cover and litter depth. Similarly, estimated surface fuel loads were nearly halved in open plots where quenda foraged compared to fenced plots where quenda were absent (3.6 cf. 6.4 Mg/ha). Fire behavior modeling, using the estimated surface fuel loads, indicated the predicted rate of spread of fire were significantly lower for open plots where quenda foraged compared to fenced plots under both low (29.2 cf. 51.4 m/h; total fuels) and high (74.3 cf. 130.4 m/h; total fuels) fire conditions. Although many environments require fire, including the bushland where this study occurred, fire management can be a considerable challenge in many landscapes, including urban bushland reserves, which are usually small and close to human infrastructure. The reintroduction of previously common digging species may have potential value as a complimentary tool for reducing fuel loads, and potentially, fire risk.


Co-use of cannabis, tobacco, and alcohol during adolescence: policy and regulatory implications.
Legislative reforms have legalized use of cannabis for medical and recreational purposes. Efforts to evaluate the public health impact of these changes have predominantly focused on determining whether liberalizing cannabis policies has increased cannabis use patterns. Co-use of cannabis and other licit substances, namely tobacco and alcohol, is common during the developmental period of adolescence, which is generally characterized by an increase in risk-taking and novelty-seeking. However, limited research has sought to evaluate the potential implications of reforms to medical and recreational cannabis laws on concurrent and simultaneous use of cannabis, tobacco, and alcohol during adolescence. The current report reviews the extant literature detailing the prevalence and outcomes associated with concurrent and simultaneous cannabis-tobacco and cannabis-alcohol use, including recent work that has examined how concurrent and simultaneous use may be influenced by cannabis reform. This review details how the cannabis landscape and cannabis retail marketplace have evolved and briefly summarizes the corresponding policy and regulatory challenges that have emerged. The report concludes with a focused cannabis co-use research agenda that adopts different strategies including behavioural economic, self-administration, and survey research methods.


L-Dopa Pharmacokinetic Profile with Effervescent Melevodopa/Carbidopa versus Standard-Release Levodopa/Carbidopa Tablets in Parkinson's Disease: A Randomised Study.
Objectives. To characterize the pharmacokinetic profile of levodopa (L-dopa) and carbidopa after repeated doses of the effervescent tablet of melevodopa/carbidopa (V1512; Sirio) compared with standard-release L-dopa/carbidopa in patients with fluctuating Parkinson's disease. Few studies assessed the pharmacokinetics of carbidopa to date. Methods. This was a single-centre, randomized, double-blind, double-dummy, two-period crossover study. Patients received V1512 (melevodopa 100 mg/carbidopa 25 mg) or L-dopa 100 mg/carbidopa 25 mg, 7 doses over 24 hours (Cohort 1), 4 doses over 12 hours (Cohort 2), or 2 doses over 12 hours in combination with entacapone 200 mg (Cohort 3). Pharmacokinetic parameters included area under the plasma-concentration time curve (AUC), maximum plasma concentration (C max), and time to C max (t max). Results. Twenty-five patients received at least one dose of study medication. L-dopa absorption tended to be quicker and pharmacokinetic parameters less variable after V1512 versus L-dopa/carbidopa, both over time and between patients. Accumulation of L-dopa in plasma was less noticeable with V1512. Carbidopa exposure and interpatient variability was lower when V1512 or L-dopa/carbidopa was given in combination with entacapone. Both treatments were well tolerated. Conclusions. V1512 provides a more reliable L-dopa pharmacokinetic profile versus standard-release L-dopa/carbidopa, with less drug accumulation and less variability. This trial is registered with ClinicalTrials.gov NCT00491998.


The Chikungunya virus: A reemerging cause of acute febrile illness in the high jungle of northern Peru.
The Chikungunya virus (CHIKV) is an emerging arthropod-borne virus (arbovirus) that causes undifferentiated acute febrile illness. Cases of CHIKV may be under-reported in Peru, given the various difficulties in diagnosing it, such as lack of diagnostic tests in remote areas, the passive nature of epidemiological surveillance, and co-circulation of other arthropod-borne pathogens. Therefore, a study was conducted in the high jungle of northern Peru to determine the prevalence of CHIKV among febrile patients and describe their clinical characteristics. A cross-sectional study was conducted in the province of Jaen, Cajamarca, located in the high jungle of northern Peru. Patients attending primary healthcare centers within Cajamarca's Regional Health Directorate were enrolled. The study took place from June 2020 through June 2021. Patients were eligible if they sought outpatient healthcare for a clinical diagnosis of acute febrile illness (AFI). Serum samples were collected from all patients, and the diagnosis of CHIKV was determined using real-time RT-PCR, as well as the detection of IgM antibodies by ELISA. A logistic regression model was employed to identify the risk factors for CHIKV, and the odds ratios (ORs) were calculated, along with their corresponding 95% confidence intervals (95% CI). A total of 1 047 patients with AFI were included during the study period. CHIKV was identified in 130 patients of 1 047 (12.4%). Among the CHIKV positive cases, 84 of 130 (64.6%) were diagnosed by RT-PCR, 42 of 130 (32.3%) by IgM ELISA detection, and 4 of 130 (3.1%) by both assays. The majority of patients with CHIKV infection fell within the 18-39 years age group (50.0%), followed by the 40-59 years age group (23.9%) and those with 60 years or older (10.8%). The most common clinical symptoms observed in patients with CHIKV infection were headache (85.4%), myalgias (72.3%), and arthralgias (64.6%). The highest number of positive CHIKV cases occurred in May (23.1%), followed by March (20.0%) and February (13.8%) of 2021. The study reports a considerable frequency of CHIKV infections among patients with AFI from the high jungle of northern Peru. These findings highlight the importance of recognizing CHIKV as an ongoing pathogen with continuous transmission in various areas of Peru. It is crucial to enhance epidemiological surveillance by implementing reliable diagnostic techniques, as the clinical symptoms of CHIKV infection can be nonspecific.


Modelling organic crystal structures using distributed multipole and polarizability-based model intermolecular potentials.
Crystal structure prediction for organic molecules requires both the fast assessment of thousands to millions of crystal structures and the greatest possible accuracy in their relative energies. We describe a crystal lattice simulation program, DMACRYS, emphasizing the features that make it suitable for use in crystal structure prediction for pharmaceutical molecules using accurate anisotropic atom-atom model intermolecular potentials based on the theory of intermolecular forces. DMACRYS can optimize the lattice energy of a crystal, calculate the second derivative properties, and reduce the symmetry of the spacegroup to move away from a transition state. The calculated terahertz frequency k = 0 rigid-body lattice modes and elastic tensor can be used to estimate free energies. The program uses a distributed multipole electrostatic model (Q, t = 00,...,44s) for the electrostatic fields, and can use anisotropic atom-atom repulsion models, damped isotropic dispersion up to R(-10), as well as a range of empirically fitted isotropic exp-6 atom-atom models with different definitions of atomic types. A new feature is that an accurate model for the induction energy contribution to the lattice energy has been implemented that uses atomic anisotropic dipole polarizability models (alpha, t = (10,10)...(11c,11s)) to evaluate the changes in the molecular charge density induced by the electrostatic field within the crystal. It is demonstrated, using the four polymorphs of the pharmaceutical carbamazepine C(15)H(12)N(2)O, that whilst reproducing crystal structures is relatively easy, calculating the polymorphic energy differences to the accuracy of a few kJ mol(-1) required for applications is very demanding of assumptions made in the modelling. Thus DMACRYS enables the comparison of both known and hypothetical crystal structures as an aid to the development of pharmaceuticals and other speciality organic materials, and provides a tool to develop the modelling of the intermolecular forces involved in molecular recognition processes.


Convergent innovation for sustainable economic growth and affordable universal health care: innovating the way we innovate.
This paper introduces convergent innovation (CI) as a form of meta-innovation-an innovation in the way we innovate. CI integrates human and economic development outcomes, through behavioral and ecosystem transformation at scale, for sustainable prosperity and affordable universal health care within a whole-of-society paradigm. To this end, CI combines technological and social innovation (including organizational, social process, financial, and institutional), with a special focus on the most underserved populations. CI takes a modular approach that convenes around roadmaps for real world change-a portfolio of loosely coupled complementary partners from the business community, civil society, and the public sector. Roadmaps serve as collaborative platforms for focused, achievable, and time-bound projects to provide scalable, sustainable, and resilient solutions to complex challenges, with benefits both to participating partners and to society. In this paper, we first briefly review the literature on technological innovation that sets the foundations of CI and motivates its feasibility. We then describe CI, its building blocks, and enabling conditions for deployment and scaling up, illustrating its operational forms through examples of existing CI-sensitive innovation.


A budget impact analysis for making treatment decisions based on anti-cyclic citrullinated peptide (anti-CCP) testing in rheumatoid arthritis.
Aim: Given that rheumatoid arthritis (RA) patients with high anti-citrullinated protein antibodies (ACPA) titer values respond well to abatacept, the aim of this study was to estimate the annual budget impact of anti-cyclic citrullinated peptide (anti-CCP) testing and treatment selection based on anti-CCP test results.Materials and methods: Budget impact analysis was conducted for patients with moderate-to-severe RA on biologic or Janus kinase inhibitor (JAKi) treatment from a hypothetical US commercial payer perspective. The following market scenarios were compared: (1) 90% of target patients receive anti-CCP testing and the results of anti-CCP testing do not impact the treatment selection; (2) 100% of target patients receive anti-CCP testing and the results of anti-CCP testing have an impact on treatment selection such that an increased proportion of patients with high titer of ACPA receive abatacept. A hypothetical assumption was made that the use of abatacept would be increased by 2% in Scenario 2 versus 1. Scenario analyses were conducted by varying the target population and rebate rates.Results: In a hypothetical health plan with one million insured adults, 2,181 patients would be on a biologic or JAKi treatment for moderate-to-severe RA. In Scenario 1, the anti-CCP test cost was $186,155 and annual treatment cost was $101,854,295, totaling to $102,040,450. In Scenario 2, the anti-CCP test cost increased by $20,684 and treatment cost increased by $160,467, totaling an overall budget increase of $181,151. This was equivalent to a per member per month (PMPM) increase of $0.015. The budget impact results were consistently negligible across the scenario analyses.Limitations: The analysis only considered testing and medication costs. Some parameters used in the analysis, such as the rebate rates, are not generalizable and health plan-specific.Conclusions: Testing RA patients to learn their ACPA status and increasing use of abatacept among high-titer ACPA patients result in a small increase in the total budget (<2 cents PMPM).


DNA microarray analysis of gene expression in response to physiological and genetic changes that affect tryptophan metabolism in Escherichia coli.
We investigated the global changes in mRNA abundance in Escherichia coli elicited by various perturbations of tryptophan metabolism. To do so we printed DNA microarrays containing 95% of all annotated E. coli ORFs. We determined the expression profile that is predominantly dictated by the activity of the tryptophan repressor. Only three operons, trp, mtr, and aroH, exhibited appreciable expression changes consistent with this profile. The quantitative changes we observed in mRNA levels for the five genes of the trp operon were consistent within a factor of 2, with expectations based on established Trp protein levels. Several operons known to be regulated by the TyrR protein, aroF-tyrA, aroL, aroP, and aroG, were down-regulated on addition of tryptophan. TyrR can be activated by any one of the three aromatic amino acids. Only one operon, tnaAB, was significantly activated by the presence of tryptophan in the medium. We uncovered a plethora of likely indirect effects of changes in tryptophan metabolism on intracellular mRNA pools, most prominent of which was the sensitivity of arginine biosynthetic operons to tryptophan starvation.


Maternal cannabis use is associated with suppression of immune gene networks in placenta and increased anxiety phenotypes in offspring.
While cannabis is among the most used recreational drugs during pregnancy, the impact of maternal cannabis use (mCB) on fetal and child development remains unclear. Here, we assessed the effects of mCB on psychosocial and physiological measures in young children along with the potential relevance of the in utero environment reflected in the placental transcriptome. Children (∼3 to 6 y) were assessed for hair hormone levels, neurobehavioral traits on the Behavioral Assessment System for Children (BASC-2) survey, and heart rate variability (HRV) at rest and during auditory startle. For a subset of children with behavioral assessments, placental specimens collected at birth were processed for RNA sequencing. Hair hormone analysis revealed increased cortisol levels in mCB children. In addition, mCB was associated with greater anxiety, aggression, and hyperactivity. Children with mCB also showed a reduction in the high-frequency component of HRV at baseline, reflecting reduced vagal tone. In the placenta, there was reduced expression of many genes involved in immune system function including type I interferon, neutrophil, and cytokine-signaling pathways. Finally, several of these mCB-linked immune genes organized into coexpression networks that correlated with child anxiety and hyperactivity. Overall, our findings reveal a relationship between mCB and immune response gene networks in the placenta as a potential mediator of risk for anxiety-related problems in early childhood.


Differential modulation of Nods signaling pathways by fatty acids in human colonic epithelial HCT116 cells.
Nucleotide-binding oligomerization domain-containing proteins (Nods) are intracellular pattern recognition receptors recognizing conserved moieties of bacterial peptidoglycan through their leucine-rich repeats domain. The agonists for Nods activate proinflammatory signaling pathways, including NF-kappaB pathways. The results from our previous studies showed that the activation of TLR4 and TLR2, leucine-rich repeat-containing pattern recognition receptors, were differentially modulated by saturated and n-3 polyunsaturated fatty acids in macrophages and dendritic cells. Here, we show the differential modulation of NF-kappaB activation and interleukin-8 (IL-8) expression in colonic epithelial cells HCT116 by saturated and unsaturated fatty acids mediated through Nods proteins. Lauric acid (C12:0) dose dependently activated NF-kappaB and induced IL-8 expression in HCT116 cells, which express both Nod1 and Nod2, but not detectable amounts of TLR2 and TLR4. These effects of lauric acid were inhibited by dominant negative forms of Nod1 or Nod2, but not by dominant negative forms of TLR2, TLR4, and TLR5. The effects of lauric acid were also attenuated by small RNA interference targeting Nod1 or Nod2. In contrast, polyunsaturated fatty acids, especially n-3 polyunsaturated fatty acids, inhibited the activation of NF-kappaB and IL-8 expression induced by lauric acid or known Nods ligands in HCT116. Furthermore, lauric acid induced, but docosahexaenoic acid inhibited lauric acid- or Nod2 ligand MDP-induced, Nod2 oligomerization in HEK293T cells transfected with Nod2. Together, these results provide new insights into the role of dietary fatty acids in modulating inflammation in colon epithelial cells. The results suggest that Nods may be involved in inducing sterile inflammation, one of the key etiological conditions in the development of many chronic inflammatory diseases.


gamma-Aminobutyric acid receptor binding in fresh mouse brain membranes at 22 degrees C: ligand-induced changes in affinity.
Binding of [3H]muscimol to mouse brain gamma-aminobutyric acid receptors has been assayed under more physiological conditions (never-frozen membranes, 22 degrees) than in previous studies (0-4 degrees on frozen-thawed membranes). Binding affinities were lower and agreed more closely with physiological dose response curves. In addition, heterogeneity in affinity was still present, apparently due to a mixture of non-interconvertible subpopulations and ligand-induced changes in kinetics. Super-high affinity sites (Kd less than 10 nM) observed in frozen membranes were not observed in fresh membranes under equilibrium binding conditions, and high affinity sites (Kd congruent to 25 nM) seen at 0 degree had lower affinity (Kd congruent to 250 nM) at 22 degrees. Despite an apparent best fit single-component Scatchard plot for the latter data, cold ligand displacement and association and dissociation rates demonstrated heterogeneity of affinities. Pentobarbital greatly increased the amount of high affinity sites at the expense of low affinity sites in equilibrium binding at 0 degree and slightly increased affinity at 22 degrees. The kinetics of [3H]muscimol association at 22 degrees (kapp = 1-2/min) were virtually independent of the ligand concentration, suggesting either negative cooperativity or an agonist binding-dependent receptor isomerization. Dissociation triggered by addition of excess cold ligand to membranes equilibrated with [3H]muscimol at different concentrations revealed two off-rates with t1/2 values of under 10 sec and 1-3 min; unexpectedly, the ratio of these two populations did not vary with ligand concentration but was constant at 50:50. Dissociation triggered by infinite dilution gave two off-rates, but the slowest component had a t1/2 of about 20 min; including cold muscimol in the dilution buffer increased the off-rate toward that observed in the excess cold ligand method (t1/2 = 1-2 min). The very slow off-rate was only observed following removal of agonist from a previously occupied receptor and suggests receptor isomerization into a high affinity state; this state is similar to that observed at 0 degree. Pentobarbital also favored the production of the receptor state showing very slow [3H]muscimol dissociation upon infinite dilution, opposing the action of high receptor occupancy with cold muscimol. Thus, [3H]muscimol-binding sites observed at 22 degrees with fresh membranes do not show artificially high affinity and have a Kd of 0.2-0.3 microM, closer to the EC50 for chloride channel activation (approximately 2-3 microM and 0.4 microM with pentobarbital).(ABSTRACT TRUNCATED AT 400 WORDS)


Comparison of amphotericin B and N-D-ornithyl amphotericin B methyl ester in experimental cryptococcal meningitis and Candida albicans endocarditis with pyelonephritis.
Amphotericin B and N-D-ornithyl amphotericin B methyl ester were compared for therapeutic efficacies against experimentally induced cryptococcal meningitis and Candida albicans endocarditis with pyelonephritis in rabbits. Antifungal activity of the two polyenes in vitro was similar for the yeasts used in these experiments. N-D-ornithyl amphotericin B methyl ester gave a slightly higher concentration in serum than amphotericin B did, but both drugs had similar elimination curves, and penetration into the cerebrospinal fluid was poor for both. Despite these similarities between the two polyenes, amphotericin B was much more effective than N-D-ornithyl amphotericin B methyl ester in the treatment of cryptococcal meningitis in rabbits. For C. albicans endocarditis, both polyenes had similar cure rates, but in vitro measurement of fungicidal activity in serum did not predict treatment outcome. For C. albicans pyelonephritis, both polyenes showed efficacy; because higher doses of the less toxic methyl ester could be used, it sterilized the urinary tract more often than amphotericin B. These studies indicate that in vivo and in vitro experiments may be needed to predict the results of treatment with polyenes.


Association of Salivary Osteopontin Levels with Glycaemic Status and Microalbuminuria - in Patients with Type 2 Diabetes Mellitus.
The monitoring of glycaemic status in patients with T2DM is mainly through blood tests (Fasting plasma glucose and HbA1c), which are invasive and involves painful pricks. This leads to poor patient compliance and soon could lead to various micro and macro vascular complications, which hamper the quality of life. There are no sensitive and specific markers to predict these complications at the earliest. Sialochemistry has recently gained attention for monitoring chronic diseases. Osteopontin is a phospho-glycoprotein molecule, elevated in many inflammatory conditions. The aim of the study was to evaluate the role of serum and salivary osteopontin in Type 2 Diabetes mellitus (T2DM). In this case-control study, we recruited 33 cases of T2DM and 31 age and gender matched healthy controls. Body Mass Index (BMI), Waist/Hip Ratio (WHR), Waist Circumference (WC) and blood pressure was recorded. Fasting Plasma Glucose (FPG), salivary glucose, HbA1c, microalbuminuria, systolic BP, serum and salivary osteopontin levels were estimated. FPG, salivary glucose, HbA1c, microalbuminuria, systolic BP, BMI, waist / hip ratio serum and salivary osteopontin levels were significantly high in T2DM cases compared to control subjects. Serum and salivary osteopontin levels were significantly correlated with HbA1c and microalbuminuria in T2DM cases. Serum and salivary osteopontin levels are significantly elevated in subjects with T2DM and are associated with glycaemic control and microalbuminuria.


A thermodynamic model for the cooperative functional properties of the tetraheme cytochrome c3 from Desulfovibrio gigas.
A thermodynamic model is presented to describe the redox behaviour of the tetraheme cytochrome c3 from Desulfovibrio gigas. This molecule displays different intrinsic redox potentials for the four hemes and during the redox titration process, interactions among different hemes occur, thus altering the values of redox potentials according to which of the hemes are oxidized [Santos, H., Moura, J.J.G., Moura, I., LeGall, J. & Xavier, A.V. (1984) Eur. J. Biochem. 141, 283-296]. This complex cooperative behaviour [Xavier, A.V. (1986) J. Inorg. Biochem. 28, 239-243] has been analyzed here using an I2H4-interaction network [Cornish-Bowden, A. & Koshland, D.E. Jr (1970) J. Biol. Chem. 245, 6241-6250] coupled to a proton-linked equilibrium between two tertiary structures. Such a formalism, which requires a reduced number of parameters, is able to fully account quantitatively for the pH dependence of the NMR redox-titration curves. The 'redox-Bohr' effect is discussed in terms of the available structure and thermodynamic data and a functional mechanism is proposed.


Spontaneous Coronary Artery Dissection with Sudden Cardiac Arrest in a Female Patient During Her Postpartum Period: A Case Report and Review.
BACKGROUND Spontaneous coronary artery dissection (SCAD) is a rare cause of acute myocardial infarction, and the literature is undecided on the etiology, predisposing factors, and susceptible populations involved. SCAD is a disease that is under-recognized, underdiagnosed, and mainly affects young women of reproductive age. It has the highest incidence in the third trimester and postpartum period. CASE REPORT We present a case of a 29-year-old woman who was brought by family members to our Emergency Department (ED) in Riyadh, Saudi Arabia with sudden cardiac arrest due to SCAD in the right coronary artery 13 days after normal spontaneous vaginal delivery. The patient was brought in with no cardiopulmonary resuscitation for 20 min. She was resuscitated successfully in the ED. Her initial rhythm was ventricular fibrillation (VF). Point-of-care ultrasound (PoCUS) was performed during pulse checks, which revealed no signs of right ventricular strain nor signs of deep vein thrombosis (DVT). After that, she underwent primary percutaneous coronary intervention, which confirmed the diagnosis of right coronary artery dissection. The patient was successfully managed and discharged from the hospital after 18 days. She was independent and in good health after 4 months of follow-up. CONCLUSIONS A high index of suspicion, familiarity with predisposing factors for SCAD, and PoCUS may play a critical role in detecting and managing SCAD patients.


New therapeutic option for thromboembolism--dabigatran etexilate.
Thrombin plays a key role in blood coagulation and haemostasis; thus its inhibition has been identified as a reasonable target to block the coagulation cascade. Direct thrombin inhibitors are potential prophylactic agents for venous thromboembolism and arterial thrombosis, which often accompany operative procedures and cardiac disease, especially orthopedic surgery and atrial fibrillation, respectively. New orally available anticoagulant agents with a wide therapeutic window are keenly anticipated because warfarin and heparins have some disadvantages, and recent progress in pharmaceutical techniques has led to the development of orally administered direct thrombin inhibitors. In this review, we discuss the usefulness of dabigatran etexilate as a new therapeutic option for preventing thromboembolism, including chemistry, pharmacokinetics, and pharmacodynamics, from the results of recent clinical studies. We systematically focused on relevant published studies, as data from recent clinical studies were difficult to obtain owing to their ongoing status. Dabigatran etexilate is a promising new oral anticoagulant that offers greatly expanded therapeutic options for both patients and physicians.


Neuropeptide Y gene polymorphisms and chronic kidney disease progression.
Neuropeptide Y (NPY) is a neurotransmitter expressed in both the central and peripheral nervous systems, which is involved in regulating a multitude of physiological processes ranging from arterial pressure, energy balance, the immune response and inflammation and renal electrolyte transport. In a cohort of chronic kidney disease (CKD) patients, we recently showed that high plasma NPY levels predict renal disease progression independently of hypertension and other risk factors but the causal nature of this association remains unproven. In the same cohort of the previous study, we tested the relationship of NPY gene variability, as assessed by five single nucleotide polymorphisms (SNPs) that explained the whole gene variability, with the incidence rate of a predefined combined renal endpoint (dialysis/transplantation/estimated glomerular filtration rate reduction >30%) over a median follow up of 36 months (inter-quartile range 35-37 months) in 735 ethnically homogeneous patients with stage 2-5 CKD. Two variants [rs16131 (recessive model for the T risk allele: TT, n = 563; CT + CC, n = 172) and rs16140 (dominant model for the G risk allele: GG + CG, n = 413; CC, n = 322)] were coherently associated with the incidence rate of renal events [hazard ratio (HR) ranging from 1.39 to 1.57, P ≤ 0.015] and this was also true when the two SNPs were jointly introduced into the same Cox model (P ≤ 0.043). The analysis of the biological interaction showed a significant synergism between the NPY rs16131 and rs16140 variants. Indeed, patients harboring NPY rs16131 TT and NPY rs16140 GG + CG risk genotypes had a much higher HR of renal events [HR: 1.80, 95% confidence interval (CI):1.16-2.79, P = 0.009] than that expected in the absence of biological interaction under both the additive and multiplicative models and the attributable proportion due to interaction (AP) was 25% and 38% on crude and adjusted analyses, respectively. This study, based on the Mendelian randomization approach and using NPY gene variants as instrumental variables to test the link between NPY and CKD progression, is in line with findings indicating that high plasma NPY levels predict an increased risk for renal events and lend support to the hypothesis that NPY is causally involved in renal disease progression.


Longitudinal Association of Nut Consumption and the Risk of Cardiovascular Events: A Prospective Cohort Study in the Eastern Mediterranean Region.
Background and Aim: There are few pieces of evidence on the association between nut consumption and the risk of cardiovascular disease (CVD) in the Eastern Mediterranean Region. This study investigated the relationship of nut consumption with the risk of CVD and all-cause mortality in the Iranian population. Methods and Results: This population-based prospective cohort study was carried out in 6,504 randomly selected participants aged ≥35 years in central Iran (2001-2013) in the framework of the Isfahan Cohort Study. Dietary data were collected by a validated 48-item food frequency questionnaire. Subjects or their next of kin were interviewed biannually, looking for the possible occurrence of cardiovascular events and all-cause mortality. During the median follow-up of 135 months and 52,704.3 person-years, we found a total of 751 CVD events. In unadjusted model, participants in the highest quartile of nut intake had a lower CVD risk {hazard ratio (HR) [95% confidence interval (CI)]: 0.57(0.47-0.70); P for trend < 0.001}, CVD mortality [HR (95% CI): 0.54 (0.33-0.72); P for trend < 0.001], and all-cause mortality [HR (95% CI): 0.24 (0.14-0.42); P for trend < 0.001]. In the fully adjusted model, the association was diluted, and no significant relationship was found between nut intake and CVD events and all-cause mortality, except for CVD mortality in the highest quartile vs. the lowest one [HR (95% CI): 0.55 (0.30-0.98)]. Conclusion: Nut intake had an inverse association with the risk of CVD mortality. It is suggested to perform studies to examine the association of individual types of nuts and different preparation methods on CVD risk and mortality.


Progression of retinopathy during pregnancy in type 1 diabetic women treated with insulin lispro.
To evaluate the progression of retinopathy during pregnancy and postpartum in (insulin-dependent) women with type 1 diabetes treated with insulin lispro or with regular human insulin. A prospective open study of 69 pregnant women with diabetes was performed. A total of 36 of the women were treated with insulin lispro (lispro group) and 33 were treated with conventional short-acting human insulin (regular insulin group). The retinopathy level was estimated by color fundus photography every trimester and postpartum. Glycemic control during pregnancy, hypoglycemia (blood glucose level <3 mmol/l) in 24-h glucose profile, blood pressure, and proteinuria were registered. HbA(1c) values were similar at baseline in the first trimester but thereafter were lower in the lispro group than in the regular insulin group throughout pregnancy (P = 0.022, repeated-measures ANOVA). The number of hypoglycemic episodes did not differ between the treatment groups. In multivariable logistic regression analysis with retinopathy severity (Diabetes Control and Complications Trial level) in the third trimester as the dependent variable, only nulliparity qualified as a predictor in the model [Exp(B) = 4.0, 95% CI 1.1-13.7, P = 0.030]. Factors such as duration of diabetes, type of insulin used, mean HbA(1c) level throughout pregnancy, blood pressure (systolic or diastolic), preeclampsia in the current pregnancy, smoking, or prepregnancy planning did not explain the retinopathy progression. Insulin lispro improves glycemic control during diabetic pregnancy compared with regular insulin with no adverse impact on progression of diabetic retinopathy.


Tet inactivation disrupts YY1 binding and long-range chromatin interactions during embryonic heart development.
Tet-mediated DNA demethylation plays an important role in shaping the epigenetic landscape and chromatin accessibility to control gene expression. While several studies demonstrated pivotal roles of Tet in regulating embryonic development, little is known about their functions in heart development. Here we analyze DNA methylation and hydroxymethylation dynamics during early cardiac development in both human and mice. We find that cardiac-specific deletion of Tet2 and Tet3 in mice (Tet2/3-DKO) leads to ventricular non-compaction cardiomyopathy (NCC) with embryonic lethality. Single-cell RNA-seq analyses reveal a reduction in cardiomyocyte numbers and transcriptional reprogramming in cardiac tissues upon Tet2/3 depletion. Impaired DNA demethylation and reduced chromatin accessibility in Tet2/3-DKO mice further compromised Ying-yang1 (YY1) binding to its genomic targets, and perturbed high-order chromatin organization at key genes involved in heart development. Our studies provide evidence of the physiological role of Tet in regulating DNA methylation dynamics and chromatin organization during early heart development.


Subcortical connections of the prefrontal cortex in dogs: afferents to the orbital gyrus.
Afferent subcortical connections to the lateral prefrontal cortex (orbital gyrus) in the dog brain were investigated using the horseradish peroxidase retrograde transport method. It was shown that: (i) the main projection to this area derives from the ventral and intermediate regions of the mediodorsal nucleus of the thalamus, (ii) fairly rich projection arises from the midline, intralaminar as well as from ventromedial and lateroposterior thalamic nuclei, (iii) scanty extrathalamic projection to the lateral prefrontal area originates from several other structures like claustrum, hypothalamus, amygdala, ventral tegmental area, raphe nuclei and locus coeruleus. Distribution of labeled cells after particular injections showed that in the orbital gyrus two subdivisions may be distinguished: dorsal and ventral. It is suggested that the dorsal orbital subdivision in dog corresponds to the lateral prefrontal cortex in monkey.


Longterm outcomes in patients with giant aneurysms secondary to Kawasaki disease.
Kawasaki disease (KD) has potentially serious cardiac complications including coronary artery aneurysms. Children who develop giant aneurysms (GA) are at increased risk of thrombosis and ischemia, and although longterm oral anticoagulation with warfarin is recommended, its efficacy has not been studied. We examined the longterm outcome of patients with GA secondary to KD, to determine if anticoagulation with warfarin aids in the prevention of myocardial ischemia. We studied patients with KD followed between May 1990 and April 2000. Thirty-nine GA occurred in 2.2% of patients with KD (22/997 patients), and 33 non-GA were also identified in these patients. Patients were divided into 2 groups, those taking warfarin and no warfarin. Most patients in both groups were also taking antiplatelet agents. The demographics of the 2 groups were statistically similar, except the median duration of followup was significantly longer for patients in the no-warfarin group (6.9 vs 13.3 yrs; p = 0.008). Four early ischemic events (< 1 year after KD diagnosis) occurred (3 myocardial infarctions and one stroke). Screening for late ischemic events by stress nuclear medicine myocardial perfusion imaging revealed only one patient, in the no-warfarin group, with reversible perfusion defects. No patient had clinical signs or symptoms of late myocardial ischemia. Echocardiographic regression of aneurysms was observed in both groups. In the warfarin vs no-warfarin group, the diameters of the GA regressed a median 22% vs 32% (p = 0.27), and non-GA regressed a median of 30% vs 25% (p = 0.61). Compliance with anticoagulation was good, and no major bleeding complication of anticoagulation occurred. Regression of GA occurred in most of our patients, and minimal late ischemia was observed. Further studies are required to evaluate the use of oral anticoagulation in patients with GA secondary to KD.


Effect of anemia in high-risk groups of patients with acute myocardial infarction treated with percutaneous coronary intervention.
The significance of anemia in patients with acute myocardial infarction (AMI) treated with percutaneous coronary intervention (PCI) remains controversial. The aim of the present study was to evaluate the effect of anemia on the short- and long-term prognosis of patients with AMI treated with PCI, including high-risk subgroups. The study group consisted of 1,497 consecutive patients with AMI treated in the acute phase with PCI. Anemia was defined using World Health Organization criteria (hemoglobin level <13 g/dl for men and <12 g/dl for women). The study population was divided into 2 major groups (patients with [n = 248, 16.6%] and without [n = 1,249, 83.4%] anemia) and 6 subgroups (diabetes mellitus, impaired renal function, age >70 years, left ventricular dysfunction, incomplete revascularization, and multivessel disease). A comparative analysis was performed between both groups within the whole population and within the particular subgroups. Significantly greater 30-day (13.2% vs 7.3%), 1-year (20.5% vs 11.3%), and total (24.1% vs 12.7%; all p <0.05) mortality rates were observed in the anemic group. Multivariate analysis identified anemia as an independent predictor of any-cause death in the whole population during the observation period (covariate-adjusted hazard ratio 1.46, 95% confidence interval 1.31 to 1.61, p <0.05). Anemia was significantly associated with excessive long-term mortality in the multivessel disease group (adjusted hazard ratio 1.54, 95% confidence interval 1.34 to 1.74) and in the incomplete revascularization group (hazard ratio 1.67, both p <0.05). In conclusion, anemia on admission in patients with AMI treated in the acute phase with PCI was independently associated with increasing short- and long-term mortality, especially in the subgroups with incomplete revascularization and multivessel disease.


The pronator compression test revisited. A forgotten physical sign.
Pronator compression testing is a valuable clinical feature of median nerve entrapment diagnosis. Of 10 patients with this disorder, all developed paresthesias preoperatively in the hand after 30 seconds or less of manual compression of the median nerve at or near the pronator muscle. Eight patients had a positive Tinel's sign at the impingement site, but only one patient had a positive electromyographic result. More than 50% of the patients had undergone previous carpal tunnel release or were diagnosed at presentation with double crush syndrome. All patients had a good or excellent result from surgical decompression of the median nerve in the forearm, except for one workers' compensation case who had excellent postoperative strength testing but multiple residual complaints. Pronator compression testing is a helpful and dependable physical sign in the diagnosis of pronator syndrome.


The use of GTX as second-line and later chemotherapy for metastatic pancreatic cancer: a retrospective analysis.
There are limited data regarding the role of second-line treatment for metastatic pancreatic cancer (mPC) after the failure of initial chemotherapy. No data exist on the use of GTX after the failure of first-line therapy. We identified patients who were given GTX chemotherapy for a diagnosis of mPC after the failure of initial therapy. Demographic features, progression-free (PFS) and overall survival (OS), response to treatment, and toxicities were recorded. The 59 evaluable patients received a median of 2 prior therapies. Three had no prior gemcitabine. Median PS was 1. Median survival was 22 weeks; progression-free survival was 9.9 weeks. Survival did not correlate with the number of prior regimens but trended with PS. There were no radiologic responses; those with stable disease (n = 21) had a better survival than those with progression (n = 29) or unevaluable patients (n = 9). Median survival was 38.3, 15.0, and 7.4 weeks, respectively. Grade 3 and 4 toxicities included leucopenia (n = 14), anemia (n = 7), and thrombocytopenia (n = 6). Hospitalizations were required in 21 patients, for febrile neutropenia (n = 7), non-neutropenic infection (n = 3), pulmonary embolus (n = 2), anemia or failure to thrive (n = 9). A 75% drop or more in CA 19-9 correlated with improved survival. GTX is an active regimen in patients previously treated with gemcitabine for mPC. Better performance status and >75% drop in pretreatment CA 19-9 were associated with longer survival. The number of prior regimens did not predict for survival duration.


Signal transduction pathways in Synechocystis sp. PCC 6803 and biotechnological implications under abiotic stress.
Cyanobacteria have developed various response mechanisms in long evolution to sense and adapt to external or internal changes under abiotic stresses. The signal transduction system of a model cyanobacterium Synechocystis sp. PCC 6803 includes mainly two-component signal transduction systems of eukaryotic-type serine/threonine kinases (STKs), on which most have been investigated at present. These two-component systems play a major role in regulating cell activities in cyanobacteria. More and more co-regulation and crosstalk regulations among signal transduction systems had been discovered due to increasing experimental data, and they are of great importance in corresponding to abiotic stresses. However, mechanisms of their functions remain unknown. Nevertheless, the two signal transduction systems function as an integral network for adaption in different abiotic stresses. This review summarizes available knowledge on the signal transduction network in Synechocystis sp. PCC 6803 and biotechnological implications under various stresses, with focuses on the co-regulation and crosstalk regulations among various stress-responding signal transduction systems.