Comparative effects of insulin and porcine somatotropin on postweaning follicular development in primiparous sows.
We compared the effects of exogenous insulin and porcine ST (pST) on follicular development after weaning. Crossbred primiparous sows received saline (1.5 mL i.m.; n = 9), insulin (.4 IU/kg BW s.c.; Eli Lilly Lente Iletin II; n = 10), or pST (40 microg/kg BW i.m.; n = 10) from d 1 to 5 after weaning (d 0). Ovaries were collected, the diameter of each follicle > or = 2 mm was measured, and fluid from the 20 largest follicles was assessed for IGF-I, IGF binding proteins (IGFBP), estradiol, progesterone, and testosterone. The total number (27.7, 25.3, and 29.1 for saline, insulin, and pST, respectively; SEM = 3.2) and average diameter (4.7, 5.2, and 5.5 mm for saline, insulin, and pST treatments, respectively; SEM = .3 mm) of ovarian follicles were not affected by insulin or pST treatment. The pST and insulin increased follicular fluid estradiol and testosterone in medium and large follicles compared to fluid from saline-treated sows, but the increase was greater for insulin than for pST treatment (treatment x size interaction, P < .01). Similarly, progesterone concentrations in follicular fluid were higher in medium and large follicles after insulin treatment, and pST treatment induced higher progesterone concentrations in small follicles and increasingly lower concentrations of progesterone in medium and large follicles (treatment x size interaction, P < .0007) compared to saline treatment. Follicular fluid IGF-I was greater (treatment x health interaction, P < .0001) in atretic and nonatretic follicles from pST-treated sows than in those from insulin- and saline-treated sows. Follicular fluid IGFBP-2 (tendency, P < .07) and IGFBP, possibly representing IGFBP-5 (30 kDa) and IGFBP-4 (22 kDa), were higher in atretic follicles than in nonatretic follicles (P < .05), whereas IGFBP-3 was not influenced by health status. The 30- and 22-kDa IGFBP were also influenced by treatment, increasing due to pST compared with saline or insulin treatments (P < .008). Follicular fluid IGFBP-2 and IGFBP-3 were not influenced by treatment. In conclusion, pST and insulin positively influenced follicular steroidogenesis and possibly follicular development, although through different mechanisms.


PatU3 plays a central role in coordinating cell division and differentiation in pattern formation of filamentous cyanobacterium Nostoc sp. PCC 7120.
Spatial periodic signal for cell differentiation in some multicellular organisms is generated according to Turing's principle for pattern formation. How a dividing cell responds to the signal of differentiation is addressed with the filamentous cyanobacterium Nostoc sp. PCC 7120, which forms the patterned distribution of heterocysts. We show that differentiation of a dividing cell was delayed until its division was completed and only one daughter cell became heterocyst. A mutant of patU3, which encodes an inhibitor of heterocyst formation, showed no such delay and formed heterocyst pairs from the daughter cells of cell division or dumbbell-shaped heterocysts from the cells undergoing cytokinesis. The patA mutant, which forms heterocysts only at the filament ends, restored intercalary heterocysts by a single nucleotide mutation of patU3, and double mutants of patU3/patA and patU3/hetF had the phenotypes of the patU3 mutant. We provide evidence that HetF, which can degrade PatU3, is recruited to cell divisome through its C-terminal domain. A HetF mutant with its N-terminal peptidase domain but lacking the C-terminal domain could not prevent the formation of heterocyst pairs, suggesting that the divisome recruitment of HetF is needed to sequester HetF for the delay of differentiation in dividing cells. Our study demonstrates that PatU3 plays a key role in cell-division coupled control of differentiation.


Reactive Molecular Dynamics Simulations of Thermal Film Growth from Di- tert-butyl Disulfide on an Fe(100) surface.
Iron sulfide films are present in many applications, including lubricated interfaces where protective films are formed through the reactions of lubricant additive molecules with steel surfaces during operation. Such films are critical to the efficiency and useful lifetime of moving components. However, the mechanisms by which films form are still poorly understood because the reactions occur between two surfaces and so cannot be directly probed experimentally. To address this, we explore the thermal contribution to film formation of di- tert-butyl disulfide-an important extreme pressure additive-on an Fe(100) surface using reactive molecular dynamics simulations, where the reactive potential parameters are validated by comparison to ab initio calculations. The reaction pathway leading to the formation of iron sulfide surfaces is characterized using the reactive simulations. Then, the film formation process is mimicked by simulations where di- tert-butyl disulfide molecules are cyclically added to the surface and subjected to temperatures comparable to those expected due to frictional heating. The use of a reactive empirical potential is a novel approach to modeling the iterative nature of thermal film growth with realistic lubricant additive molecules.


Zygomycosis: the re-emerging fungal infection.
Invasive fungal infections are major medical complications in immunocompromised patients. The recent rise in the incidence of cancer and the increased use of newer medical treatment modalities, including organ transplantations, have resulted in growing numbers of highly immunosuppressed individuals. Although aspergillosis and candidiasis are among the most common invasive mycoses in such patients, there is evidence that the incidence of infectious diseases caused by Zygomycetes has risen significantly over the past decade. Patients with diabetes, malignancies, solid organ or bone marrow transplants, or iron overload and those receiving immunosuppressive agents, deferoxamine therapy, or broad-spectrum antimicrobial drugs are at highest risk for zygomycosis. This review details the emergence and importance of zygomycosis in current clinical practice and its manifestations and management. The etiologic species, pathogenesis and risk factors for zygomycosis are reviewed and updated. The clinical spectrum of zygomycosis is now broader, and it can be difficult to distinguish between mucormycosis and enthomophthoramycosis, both of which can manifest as disease ranging from a superficial infection to an angioinvasive infection with high mortality. Finally, the three-part treatment strategy (antifungal drugs, surgery, control of underlying diseases) is reviewed. Lipid formulations of amphotericin B are the antifungal agents of choice for treatment of zygomycosis. A novel antifungal triazole, posaconazole, has been developed and may become approved for treatment of zygomycosis. The clinical experience with adjunctive treatments like colony-stimulating factors, interferon-gamma, and hyperbaric oxygen therapy is still limited.


Comparative velocities of different types of fast eye movements in man.
The peak velocity-amplitude characteristics of voluntary saccades and the fast phases of caloric, rotational, and optokinetic (OKN) nystagmus were compared in ten human subjects in both light and, except for OKN, darkness. All these fast eye movements had similar velocities and all slowed in darkness. This study supports the presumption that the identical brainstem firing patterns found in monkeys for all fast eye movements also occur in man.


Infectivity of liposomally encapsulated nucleic acids isolated from EMC virus and scrapie-infected mouse brain.
The ability of liposomes to enhance nucleic acid infectivity in vivo was studied. Encephalomyocarditis (EMC) virus RNA was extracted and encapsulated within liposomes. The infectivity of EMC RNA was increased by liposomal entrapment after intraperitoneal injection of mice, but decreased after intracerebral injection. In contrast, when nucleic acids from scrapie-infected brains were entrapped in liposomes and injected into mice by one of four routes, no cases of scrapie were observed. This is the first report of the enhancement of nucleic acid infectivity by liposomes in vivo.


Performance evaluation results of evolutionary clustering algorithm star for clustering heterogeneous datasets.
This article presents the data used to evaluate the performance of evolutionary clustering algorithm star (ECA*) compared to five traditional and modern clustering algorithms. Two experimental methods are employed to examine the performance of ECA* against genetic algorithm for clustering++ (GENCLUST++), learning vector quantisation (LVQ), expectation maximisation (EM), K-means++ (KM++) and K-means (KM). These algorithms are applied to 32 heterogenous and multi-featured datasets to determine which one performs well on the three tests. For one, ther paper examines the efficiency of ECA* in contradiction of its corresponding algorithms using clustering evaluation measures. These validation criteria are objective function and cluster quality measures. For another, it suggests a performance rating framework to measurethe the performance sensitivity of these algorithms on varos dataset features (cluster dimensionality, number of clusters, cluster overlap, cluster shape and cluster structure). The contributions of these experiments are two-folds: (i) ECA* exceeds its counterpart aloriths in ability to find out the right cluster number; (ii) ECA* is less sensitive towards dataset features compared to its competitive techniques. Nonetheless, the results of the experiments performed demonstrate some limitations in the ECA*: (i) ECA* is not fully applied based on the premise that no prior knowledge exists; (ii) Adapting and utilising ECA* on several real applications has not been achieved yet.


[Morphological and biochemical changes in the myocardium after sudden death from ischemic heart disease].
The myocardium was examined in 44 persons who had suddenly died of ischemic heart disease, in 37 who had died of injury, and in 28 who had died of alcohol poisoning. Those with ischemic heart disease had foci of necrosis of the muscle fibers, severe disturbances in microcirculation, changes in the activity of certain myocardial enzymes and in the content of lipids in the myocardium. Biochemical changes similar to these in many respects were revealed in individuals who had died of alcohol poisoning, in view of which alcohol poisoning may be a factor conducive to sudden death in ischemic heart disease.


Degradation of myofibrillar proteins by extractable lysosomal enzymes and m-calpain, and the effects of zinc chloride.
A study was conducted to examine the effects that physiological levels of m-calpain (calpain requiring millimolar concentrations of Ca2+) extract and a lysosomal extract have on myofibrillar proteins in vitro, and the effects that zinc has on inhibiting proteolysis by these extracts. During a 22-h incubation period, the lysosomal extract degraded myosin heavy chain, alpha-actinin, desmin, troponin-I, and myosin light chains 1 and 2. The effectiveness of the lysosomal extract to degrade myofibrillar proteins was significantly affected by the presence or absence of EDTA. Zinc, which is a potent inhibitor of cysteine proteinases, prevented most, but not all, of the lysosomal extract-induced myofibrillar protein degradation. Incubation of myofibrils with m-calpain resulted in the hydrolysis of troponin-T, desmin, and a 58-kDa molecular weight protein, possibly vimentin, and 5 mM ZnCl2 completely blocked these changes. Results from this study indicate that the degradation by the lysosomal extract is far more extensive than the degradation that occurs with normal postmortem storage and that possibly a non-cysteine protease is present that is capable of hydrolyzing some myofibrillar proteins under this in vitro condition, because Zn2+ did not block all proteolysis. However, similar changes were induced by m-calpain incubation and postmortem storage.


Simulations of dipolar fluids using effective many-body isotropic interactions.
The partition function of a system with pairwise-additive anisotropic dipole-dipole interactions is equal to that of a hypothetical system with many-body isotropic interactions [G. Stell, Phys. Rev. Lett. 32, 286 (1974)]. The effective many-body interactions contain n-body contributions of all orders. Each contribution is known as an expansion in terms of the particle-particle distances r, and the coefficients are temperature dependent. The leading-order two-body term is the familiar -r(-6) attraction, and the leading-order three-body term is equivalent to the Axilrod-Teller interaction. In this work, a fluid of particles with the leading-order two-body and three-body interactions is compared to an equivalent dipolar soft-sphere fluid. Molecular simulations are used to determine the conditions under which the effective many-body interactions reproduce the fluid-phase structures of the dipolar system. The effective many-body interaction works well at moderately high temperatures but fails at low temperatures where particle chaining is expected to occur. It is shown that an adjustment of the coefficients of the two-body and three-body terms leads to a good description of the structure of the dipolar fluid even in the chaining regime, due primarily to the ground-state linear configuration of the three-body Axilrod-Teller interaction. The vapor-liquid phase diagrams of systems with different Axilrod-Teller contributions are determined. As the strength of the three-body interaction is increased, the critical temperature and density both decrease and disappear completely above a threshold strength, where chaining eventually suppresses the condensation transition.


Assessment of three-dimensional biofilm models through direct comparison with confocal microscopy imaging.
The mathematical modeling of spatial biofilm formation that provides the capability to predict biofilm structure from first principles has been in development for the past six years. However, a direct and quantitative link between model predictions and the experimentally observed structure formation still remains to be established. This work assesses the capability of a state-of-the-art technique for three-dimensional (3D) modeling of biofilm structure, individual based modeling (IbM), to quantitatively describe the early development of a multispecies denitrifying biofilm. Model evaluation was carried out by comparison of predicted structure with that observed from two experimental datasets using confocal laser scanning microscopy (CLSM) monitoring of biofilm development in laboratory flowcells. Experimental conditions provided biofilm growth without substrate limitation, which was confirmed from substrate profiles computed by the model. 3D structures were compared quantitatively using a set of morphological parameters including the biovolume, filled-space profiles, substratum coverage, average thickness and normalized roughness. In spite of the different morphologies detectable in the two independent short-term experiments analyzed here, the model was capable of accurate fitting data from both experiments. Prediction of structure formation was precise, as expressed by the set of morphology parameters used.


Motor control of voluntary trunk movements in standing.
The pattern of activity in different trunk muscles during voluntary trunk movements was studied in the standing position in man. The electromyographic activity from ventral and dorsal trunk muscles on the left and right sides were recorded together with the movements in the sagittal and frontal planes (Selspot optoelectronic system). Movement direction, amplitude, velocity and initial posture were varied. In all movements there was a basic pattern of alternation between antagonist muscle groups. Fast movements were initiated by a sharp burst of activity, whereas slow flexions and side bendings resulted from a decrease in antigravity muscle activity. Movement amplitude was related to the magnitude of the initiating burst, and also to the time of onset of antagonist muscle activity with a braking effect. The contribution of passive internal forces in the braking of a movement was indicated by the myoelectrical pattern of activity, particularly in slow large side bendings, where ipsilateral activity was present at the end of the movement. Sagittal movements starting at different initial trunk inclinations resulted in shifts in onset time and duration between antagonist muscles. The observed modifications are specific adaptations of the motor program to balance changes in mechanical conditions, such as angular acceleration, moment arm for the gravitational force, and intrinsic forces of active and passive structures surrounding the spine and pelvis. In conclusion, the present results demonstrate that trunk movements are generated and controlled by specific patterns of muscle coordination.


Open surgical management of complications from indwelling radial artery catheters.
Cannulation of the radial artery is frequently performed for invasive hemodynamic monitoring. Complications arising from indwelling catheters have been described in small case series; however, their surgical management is not well described. Understanding the presentation and management of such complications is imperative to offer optimal treatment, particularly because the radial artery is increasingly accessed for percutaneous coronary interventions. We conducted a retrospective review to identify patients who underwent surgical intervention for complications arising from indwelling radial artery catheters from 1997 to 2011. We identified 30 patients who developed complications requiring surgical intervention. These complications were categorized into ischemic and nonischemic, with 15 patients identified in each cohort. All patients presenting with clinical hand or digital ischemia underwent thrombectomy and revascularization. Complications in the nonischemic group included three patients with deep abscesses with concomitant arterial thrombosis, two with deep abscesses alone, and 10 with pseudoaneurysms. Treatment strategy in this group varied with the presenting pathology. Among the entire case series, three patients required reintervention after the initial surgery, all in individuals initially presenting with ischemia who developed recurrent thrombosis of the radial artery. There were no digital or hand amputations in this series. However, the overall in-hospital mortality in these patients was 37%, reflecting the severity of illness in this patient cohort. Three patients who were positive for heparin-induced thrombocytopenia antibody had 100% mortality compared with those who were negative (P = .04, Fisher exact test). In-hospital mortality was higher in patients presenting with initial ischemia than in those with nonischemic complications (53% vs 20%; P = .06). Among 10 patients who presented with pseudoaneurysms, five (50%) were septic at presentation with positive blood cultures, and six (60%) had positive operating room cultures. Staphylococcus aureus was identified as the causative organism in all of these patients. Complications of radial artery cannulation requiring surgical intervention can represent infectious and ischemic sequelae and have the potential to result in major morbidity, including digital or hand amputation and sepsis, or death. Although surgical treatment is successful and often required in these patients to treat severe hand ischemia, hemorrhage, or vascular infection, these complications tend to occur in critically ill hospitalized patients with an extremely high mortality. This must be taken into consideration when planning surgical intervention in this patient cohort. Finally, radial arterial cannulation sites should not be overlooked when searching for occult septic sources in critically ill patients.


Disseminated intravascular coagulation in term and preterm neonates.
Among critically ill patients, the risk of developing disseminated intravascular coagulation (DIC) is probably highest in neonates. Low plasma reserves in pro- and anticoagulant coagulation factors, intravascular volume contraction after birth, and a high incidence of hypoxia and sepsis in critically ill newborns rapidly lead to a decompensation of the coagulation system in this population. Global coagulation tests and single-factor plasma levels have to be interpreted in the context of age-corrected normal ranges. Platelet consumption and reduced protein C plasma levels have diagnostic value; the latter also has prognostic potential in neonates with DIC and sepsis. Therapeutic success relies heavily on reversal of the underlying condition. Some coagulation-specific therapies have been explored in small studies and case series with varying success and sometimes conflicting results. Therefore, larger controlled trials in this common and serious condition are urgently needed.


Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pulmonary arterial hypertension associated with connective tissue diseases.
The explosive growth of medical literature on pulmonary hypertension (PH) has led to a steady increase in awareness of this disease within the medical community during the past decade. The recent revision of the classification of PH is presented in in the main guidelines. Group 1 PH or pulmonary arterial hypertension (PAH) is a heterogeneous group and includes PH due to inheritable, drug-induced, and toxin-induced causes and to such underlying systemic causes as connective tissue diseases, human immunodeficiency viral infection, portal hypertension, congenital heart disease, and schistosomiasis. Systemic sclerosis (SSc) is an autoimmune multisystem disorder, which affects over 240 persons per million in the United States.[1] Its manifestations are not confined to the skin but may also involve the lungs, kidneys, peripheral circulation, musculoskeletal system, gastrointestinal tract, and heart. The outcome of PAH associated with SSc is worse when compared to other subtypes of PAH. In this review, we summarize available information about the pulmonary vascular and cardiac manifestations of SSc with special emphasis on their prognostic implications as well as the peculiarity of their detection.


[Effect of vitamin E deficiency and of qualitatively varying dietary fats on the structure of the aorta and of the heart and kidney arteries in rats].
Rats kept for 8 months on vitamin E deficient diet or given butter in an amount of 50 % of the diet caloric value developed similar morphological changes in aortal walls and in intraorgan arteries of the heart and kidneys. These changes marked by derangement of the elastic base of the vascular wall were most pronounced in rats kept on E-avitaminosis diet. In these animals changes in vascular elasticity developed in the presence of the intima edema, occasionally, of the media, formation of the thickening of the vascular wall, appearance of calcinosis areas in it. As a rule, changes in coronary vessels were associated with myocardial structure impairment manifesting in the form of foci of necrosis in the muscle layer, in reparative cellular reaction and foci of substitution sclerosis.


Evaluation of bacterial and fungal contamination in the health care workers' hands and rings in the intensive care unit.
Nosocomial infections remain a major challenge to the health care system and result in significant mortality, morbidity, and economic burden. Intensive care unit (ICU) patients are at great risk of acquiring nosocomial infections. The objective of this study was to determine the contamination rate (bacterial and fungal) of the health care workers' (HCWs') hands and ring in ICU. All health care workers were screened during the day shift in Emam hospital ICU. After obtaining informed consent, convenience samples of HCWs' hands and rings were cultured on specific media during their routine work hours, always after a patient care episode. The fungal and bacterial isolates were identified using standard microbiological procedures. A total of 40 subjects were selected in this study (28 females, 12 males). The rate of contamination of hands and rings was observed in 73.1%. Most of isolates are known to cause nosocomial infections which included: 23% staphylococci, 7.9% Klebsiella spp., 4.7% Enterobacter spp., 3.9% Escherichia coli, 3.1% Acinetobacter spp., 2.3% Pseudomonas spp., and 27.7% were colonized with fungi. The fungal isolates were 16.6% Candida spp., 3.9% Rhodotorula spp., 3.1% Aspergillus niger, and 3.9% Aspergillus flavus. According to these results HCWs' hands and their rings were contaminated with various types of microorganisms. Medical and hospital personals must follow careful hand-washing techniques to minimize transmission of disease and should remove rings, watches, and bracelets before washing their hands and entering the ICU.


Minimization of eddy current artifacts in sequences with periodic dynamics.
To minimize eddy current artifacts in periodic pulse sequences with balanced gradient moments as, for example, used for quantitative MRI. Eddy current artifacts in balanced sequences result from large jumps in k-space. In quantitative MRI, one often samples some spin dynamics repeatedly while acquiring different parts of k-space. We swap individual k-space lines between different repetitions in order to minimize jumps in temporal succession without changing the overall trajectory. This reordering can be formulated as a traveling salesman problem and we tackle the discrete optimization with a simulated annealing algorithm. Compared to the default ordering, we observe a substantial reduction of artifacts in the reconstructed images and the derived quantitative parameter maps. Comparing two variants of our algorithm, one that resembles the pairing approach originally proposed by Bieri et al., and one that minimizes all k-space jumps equally, we observe slightly lower artifact levels in the latter. The proposed reordering scheme effectively reduces eddy current artifacts in sequences with balanced gradient moments. In contrast to previous approaches, we capitalize on the periodicity of the sampled signal dynamics, enabling both efficient k-space sampling and minimizing artifacts caused by eddy currents.


Factors involved in gas embolism after laparoscopic injury to inferior vena cava.
This study evaluated the incidence and factors involved in the occurrence of gas embolism after laparoscopic injuries. A 5-MHz transesophageal echocardiographic (TEE) probe was placed in 11 anesthetized pigs and used to examine the right cardiac chambers and pulmonary artery. A calibrated carbon dioxide analyzer continuously measured end-tidal carbon dioxide (ETCO2). The ventilatory settings were adjusted to achieve a baseline ETCO2 between 25 and 28 mm Hg. A blinded dose-response curve for TEE and ETCO2 measurements were created by injecting 0.0007 to 1.5 mL/kg of CO2 gas intravenously. Venotomies (N = 22) were created laparoscopically in the inferior vena cava (IVC) of the study animals. All TEE images were videotaped and correlated with laparoscopic events. Embolic episodes were classified by comparison with images recorded during the bolus studies. A variety of methods for obtaining hemostasis and repairing the venotomies were evaluated and their effects on gas embolism were studied. No emboli were noted when the venotomies were bleeding freely, the hole was directly occluded, or the proximal IVC was compressed. Marked embolism was seen with distal IVC occlusion or when there had been significant blood loss. In this situation, manipulation of the hole and higher intraperitoneal pressures led to higher degrees of embolization. No emboli were seen in an open control group except after significant bleeding. The TEE is the most sensitive method of detecting gas emboli; however, the majority of episodes are not clinically significant. Embolism of CO2 occurs when central venous pressure is decreased by blood loss or distal compression. When significant venous bleeding occurs, intravascular volume should be maintained and the bleeding site should be directly occluded.


Accelerated volatilization rates of selenium from different soils.
Selenium (Se), an element found naturally in a variety of soils, can accumulate in drainage water of lands under intensive irrigation, even reaching levels that are toxic to mammals and birds. Volatilization of Se by soil microorganisms into dimethylselenide (DMSe) can be enhanced by certain soil amendments and, thus, be used as a soil remediation process. In an 8-wk laboratory study, five soils from California and one from Germany were spiked with 75SeO3(2-) (22.3 mg/kg Se). Two amino acids (DL-homocysteine and L-methionine), a carbohydrate (pectin), and a protein (zein) were tested as soil amendments. Gaseous 75Se emissions were trapped with activated carbon and measured in a gamma counter. Depending on soil type, the cumulative volatilization from the control flasks varied between 1.2% and 9.0% of applied 75Se. Both zein and L-methionine strongly increased volatilization (max. 43% of 75Se applied), whereas DL-homocysteine had a much smaller stimulating effect. Pectin showed a moderate effect, but enhanced Se volatilization rates were sustained much longer when compared to the zein amendment. Volatilization rates of Se followed a simple first-order reaction. Gaseous Se emission in the soils treated with L-methionine yielded an S-shaped curve, which fit a growth-modified first-order rate model. Although zein and L-methionine were the most favorable treatments enhancing Se volatilization, all six soils responded differently to the soil amendments.


Bone markers and osteoporosis therapy.
Several factors are involved in determining bone quality including bone density, bone turnover, the extent of trabecular bone connectivity, cortical porosity and geometry. Metabolically active and in a continuous process of remodeling, approximately 20% of bone tissue is renewed annually. Bone turn over markers (BTM) are frequently used in clinical trials and to provide valid information about the effectiveness of osteoporosis treatment, reflecting the state of bone metabolism and its response to treatment, although they are not useful alone to estimate bone loss. In this review the behavior of BTM from different clinical trials or different osteoporotic drugs will be addressed.


The effects of aripiprazole on the subscales of the Kellner Symptom Questionnaire in treatment resistant depression.
We have recently examined the efficacy of low-dose aripiprazole augmentation for major depressive disorder (MDD), with modest nonsignificant benefit found. In a secondary investigation, we examined whether aripiprazole resulted in improvement in four subscales (depression, anxiety, somatic symptoms, and hostility) of the Kellner Symptom Questionnaire (KSQ). We reanalyzed data from the main outcome study on 221 MDD patients with inadequate response to selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. Patients were randomized, using the sequential parallel comparison design, into two 30-day phases, as follows: drug/drug (aripiprazole 2 mg/day in phase 1, aripiprazole 5 mg/day in phase 2), placebo/drug (placebo in phase 1, aripiprazole 2 mg/day in phase 2), or placebo/placebo (placebo in both phases). We examined changes in the KSQ score from baseline to endpoint on the basis of the subscaled Well-being and Reversal Distressed Anxiety Subscales. The score for the KSQ depression subscale improved from baseline to the end of follow-up, with a significant advantage for aripiprazole over placebo (P=0.0327). Although improvement was also observed in the anxiety and hostility scales, neither attained a significant advantage over placebo; no significant change was observed for the somatization subscale. Aripiprazole augmentation resulted in a significant improvement compared with placebo augmentation only in the depression subscale of the KSQ; however, the low dose may not have been enough to have an impact on the anxiety and hostility scales. The good tolerability of the low dose may have resulted in the absence of worsening of somatic symptoms. Prospective studies are needed to better characterize the impact of low doses of aripiprazole augmentation on different manifestations of MDD.


Endoscopic transluminal pancreatic necrosectomy using a self-expanding metal stent and high-flow water-jet system.
Walled-off pancreatic necrosis and a pancreatic abscess are the most severe complications of acute pancreatitis. Surgery in such critically ill patients is often associated with significant morbidity and mortality within the first few weeks after the onset of symptoms. Minimal invasive approaches with high success and low mortality rates are therefore of considerable interest. Endoscopic therapy has the potential to offer safe and effective alternative treatment. We report here on 3 consecutive patients with infected walled-off pancreatic necrosis and 1 patient with a pancreatic abscess who underwent direct endoscopic necrosectomy 19-21 d after the onset of acute pancreatitis. The infected pancreatic necrosis or abscess was punctured transluminally with a cystostome and, after balloon dilatation, a non-covered self-expanding biliary metal stent was placed into the necrotic cavity. Following stent deployment, a nasobiliary pigtail catheter was placed into the cavity to ensure continuous irrigation. After 5-7 d, the metal stent was removed endoscopically and the necrotic cavity was entered with a therapeutic gastroscope. Endoscopic debridement was performed via the simultaneous application of a high-flow water-jet system; using a flush knife, a Dormia basket, and hot biopsy forceps. The transluminal endotherapy was repeated 2-5 times daily during the next 10 d. Supportive care included parenteral antibiotics and jejunal feeding. All patients improved dramatically and with resolution of their septic conditions; 3 patients were completely cured without any further complications or the need for surgery. One patient died from a complication of prolonged ventilation severe bilateral pneumonia, not related to the endoscopic procedure. No procedure related complications were observed. Transluminal endoscopic necrosectomy with temporary application of a self-expanding metal stent and a high-flow water-jet system shows promise for enhancing the potential of this endoscopic approach in patients with walled-off pancreatic necrosis and/or a pancreatic abscess.


Responsiveness of upper extremity kinematic measures and clinical improvement during the first three months after stroke.
Kinematic movement analysis is increasingly used as an outcome measure in evaluation of upper extremity function after stroke. Little is known, however, about what observed longitudinal changes in kinematics mean in the context of an individual's functioning. In this study, the responsiveness and expected change in kinematic measures associated with clinically meaningful improvement in the upper extremity were evaluated. . Kinematic movement analysis of a drinking task and Action Research Arm Test (ARAT) were performed early (9 days poststroke) and at 3 months after stroke in 51 subjects. The receiver-operating characteristic curve and linear regression analyses were used to evaluate responsiveness of kinematic parameters. Movement time, smoothness, and trunk displacement discriminated those subjects demonstrating clinically meaningful improvements. Significant associations of 31% to 36% were found between the change in ARAT and kinematic measures. A real clinical improvement in kinematics lies in the range of 2.5 to 5 seconds, 3 to 7 units, and 2 to 5 cm in movement time, smoothness, and trunk displacement, respectively. All kinematic measures reported in this study are responsive measures for capturing improvements in the upper extremity during the first 3 months after stroke. Approximate estimates for the expected change in kinematics associated with clinically meaningful improvement in upper extremity activity capacity illustrate the usefulness of the linear regression analysis for assessing responsiveness. This knowledge facilitates the selection of kinematic measures for clinical and movement analysis research as well as for technology-based devices.


Measurement of aortic regurgitation by Doppler echocardiography.
In an attempt to develop a new approach to the non-invasive measurement of aortic regurgitation, transmitral volumetric flow (MF) and left ventricular total stroke volume (SV) were measured by Doppler and cross sectional echocardiography in 23 patients without aortic valve disease (group A) and in 26 patients with aortic regurgitation (group B). The transmitral volumetric flow was obtained by multiplying the corrected mitral orifice area by the diastolic velocity integral, and the left ventricular total stroke volume was derived by subtracting the left ventricular end systolic volume from the end diastolic volume. The aortic regurgitant fraction (RF) was calculated as: RF = 1 - MF/SV. In group A there was a close agreement between the transmitral volumetric flow and the left ventricular total stroke volume, and the difference between the two measurements did not differ significantly from zero. In group B the left ventricular total stroke volume was significantly larger than the transmitral volumetric flow, and there was good agreement between the regurgitant fractions determined by Doppler echocardiography and radionuclide ventriculography. Discrepancies between the two techniques were found in patients with combined aortic and mitral regurgitation or a low angiographic left ventricular ejection fraction (less than 35%). The effective cardiac output measured by Doppler echocardiography accorded well with that measured by the Fick method. Doppler echocardiography provides a new and promising approach to the non-invasive measurement of aortic regurgitation.


Social isolation in Asian Americans: risks associated with socio-demographic, health, and immigration factors.
The present study examined the factors associated with social isolation in Asian Americans. Three types of social isolation (social isolation from family, social isolation from friends, and overall social isolation), identified by the Lubben Social Network Scale-6, were examined with a sample of Asian Americans representing diverse ethnic groups (Chinese, Asian Indian, Korean, Vietnamese, Filipino, and other Asians) and a broad age range (18-98). Using data from the 2015 Asian American Quality of Life Survey (N = 2609), logistic regression models examined how each type of social isolation was predicted by sociodemographic (age, gender, ethnic origin, marital status, education, and perceived financial status), health-related (chronic medical conditions and self-rated health), and immigration-related (proportion of life in the United States and English proficiency) variables. The percentage of the sample that fell into the category of social isolation from family, social isolation from friends, and overall isolation ranged from 18.2% to 19.3%. At 36% in the friend category and 33% in the overall category, the Vietnamese sample showed a heightened risk of social isolation. Regression analyses indicated that, for both family and friend categories, individuals who were in the middle-aged group (40-59 years old) and who had limited English proficiency demonstrated higher odds of being isolated. Reflecting relational differences in family and friend networks, the risk associated with unmarried status was specific to social isolation from family, whereas having unmet financial needs was only associated with social isolation from friends. The study findings expand our understanding of the multiple domains of social isolation in an understudied population and emphasize the importance of developing prevention and intervention programs to foster social connectedness among Asian Americans. Our findings on risk factors and ethnic variations help identify the groups to be prioritized in intervention efforts and suggest ways to approach them.


Hyperthermic intraperitoneal doxorubicin: pharmacokinetics, metabolism, and tissue distribution in a rat model.
The cytotoxic effect of several anticancer agents, including doxorubicin, can be enhanced by hyperthermia. The purpose of this study was to evaluate the effect of hyperthermia on the pharmacokinetics, metabolism, and tissue distribution of intraperitoneal (i.p.) doxorubicin in a rodent model. Doxorubicin was given i.p. to 20 Sprague-Dawley rats at a dose of 2 mg/kg over 60 min. Rats were randomized into two groups according to the temperature of the peritoneal perfusate: group NT received normothermic (37 degrees C) i.p. doxorubicin; group HT received hyperthermic (43 degrees C) i.p. doxorubicin. During the course of i.p. chemotherapy, peritoneal fluid and blood were sampled every 10 min. At the end of the procedure, rats were sacrificed and tissue samples (liver, spleen, small bowel, omentum, bladder, diaphragm, abdominal wall, heart) were collected. Concentrations of doxorubicin and its aglycone metabolites were determined in peritoneal fluid, plasma, and tissues by HPLC. No significant differences in areas under the curve (AUC) of peritoneal fluid doxorubicin and plasma doxorubicin were found between group NT and group HT. AUC ratios (AUC peritoneal fluid/AUC blood) were 87.9 for group NT and 82.9 for group HT. Group HT exhibited increased doxorubicin concentrations for all intraabdominal tissues. These differences were significant for spleen (P = 0.03), small bowel (P = 0.03), and omentum (P = 0.03). Doxorubicin aglycone was detected in plasma of both groups within the first 10 min of the procedure. There was a significant (P < 0.001) increase in plasma aglycone AUC for group HT when compared with group NT. Group HT exhibited increased aglycone concentration for all tissues. This difference was significant for liver (P < 0.001) and bladder (P < 0.001). Hyperthermia did not affect significantly the pharmacokinetics of i.p. doxorubicin. Tissue concentrations of doxorubicin in small bowel, omentum, and spleen were significantly increased when the drug was administered by hyperthermic i.p. perfusion. Hyperthermia increased significantly the doxorubicin aglycone concentrations in plasma, liver, and bladder.


[Parapsoriasis en plaques. Characterization of the cellular infiltrate using monoclonal antibodies].
We report on a 65-year old woman suffering from parapsoriasis with large plaques. The cellular infiltrate was analysed by means of monoclonal antibodies and an immunoperoxidase technique. Our findings proved that the majority of the cellular infiltrate in the upper dermis is composed of helper-inducer T-cells (Leu 4+, Leu 3a+). A notable number of Leu-2a-reactive suppressor-cytotoxic T-cells associated with hydropic degeneration of the basal cell layer were found within the dermal infiltrate and the dermoepidermal interface. Large numbers of Leu-6-reactive dendritic Langerhans' cells were noted in the lower layers of the epidermis, in particular in areas where the epidermis showed focal exocytosis of lymphoid cells. Langerhans' cells, in contrast, were present in the upper portions of epidermis lacking exocytic T-cells. HLA-DR antigens were expressed on Langerhans' cells as well as on nearly all T-lymphocytes. Positive intercellular staining for HLA-DR antigens were only found in localized areas of the epidermis. Small numbers of both Leu-11B-reactive natural killer cells and cells expressing interleukin-2 receptors were seen within the basal cell layer and at the dermo-epidermal junction. Our findings suggest that a cell-mediated immune response which is directed against antigens expressed by keratinocytes may play an important role in the pathogenesis of parapsoriasis en plaques.


Influence of exposure and infusion times on the cytotoxicity and pharmacokinetics of cis-malonato[(4R, 5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) .
The effect of exposure time on the in vitro cytotoxicity of a new platinum complex, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolan e]platinum(II) (SKI 2053R) and cisplatin (CDDP) toward two human lung-adenocarcinoma cell lines (PC-9, PC-14) and two human stomach-adenocarcinoma cell lines (KATO III, MKN-45) was investigated by variation of the exposure time (1, 4, 12, and 24 h) and drug concentration to yield a constant product of drug concentration times exposure time (C x T). Exposure of cancer cells to low concentrations of SKI 2053R for 12 or 24 h resulted in a greater killing effect than did 1- or 4-h exposure to 24- or 6-fold higher concentrations; the inhibitory effects of SKI 2053R on the colony formation of all tumor cell lines except for KATO III were significantly increased with increasing exposure time (P < 0.05). However, the inhibitory effects of CDDP against all tumor cell lines tested except for PC-14 were inversely correlated with increasing exposure time (P < 0.05). The intracellular accumulation of SKI 2053R and CDDP was measured under the same conditions used in the cell-survival assay using MKN-45 cells. The amount of platinum accumulated from SKI 2053R into MKN-45 cells was greater for the treatment involving low concentrations and long-term exposures (12 and 24 h) than for that using high concentrations and short-term exposures (1 and 4 h) at the constant C x T values; however, the increased accumulation of CDDP was more prominent as the concentration was increased, even if the exposure time became shorter. The pharmacokinetics studies of SKI 2053R following 1-, 4-, 12-, and 24-h infusions were performed in beagle dogs. A single dose of SKI 2053R (5.0 mg/kg) was successively given over various infusion periods to three beagle dogs at 3-week intervals. The peak levels of ultrafiltrable platinum observed for SKI 2053R at the 1-, 4-, 12-, and 24-h infusions were 3.10+/-0.49 (mean +/- SD), 1.24+/-0.06, 0.43+/-0.07, and 0.25+/-0.04 microg/ml, respectively. The mean binding ratios of platinum from SKI 2053R to plasma protein at the end of 1-, 4-, 12-, and 24-h infusions were approximately 91%, 73%, 53%, and 51%, respectively. The steady-state level of free platinum was maintained during long-term infusions (12 and 24 h) after short periods (1-3 h) from the start of the infusion. This study strongly suggests that the therapeutic efficacy of SKI 2053R given by continuous long-term infusion should be investigated in future clinical studies.


Quantitative analysis of axonal fiber activation evoked by deep brain stimulation via activation density heat maps.
Cortical modulation is likely to be involved in the various therapeutic effects of deep brain stimulation (DBS). However, it is currently difficult to predict the changes of cortical modulation during clinical adjustment of DBS. Therefore, we present a novel quantitative approach to estimate anatomical regions of DBS-evoked cortical modulation. Four different models of the subthalamic nucleus (STN) DBS were created to represent variable electrode placements (model I: dorsal border of the posterolateral STN; model II: central posterolateral STN; model III: central anteromedial STN; model IV: dorsal border of the anteromedial STN). Axonal fibers of passage near each electrode location were reconstructed using probabilistic tractography and modeled using multi-compartment cable models. Stimulation-evoked activation of local axon fibers and corresponding cortical projections were modeled and quantified. Stimulation at the border of the STN (models I and IV) led to a higher degree of fiber activation and associated cortical modulation than stimulation deeply inside the STN (models II and III). A posterolateral target (models I and II) was highly connected to cortical areas representing motor function. Additionally, model I was also associated with strong activation of fibers projecting to the cerebellum. Finally, models III and IV showed a dorsoventral difference of preferentially targeted prefrontal areas (models III: middle frontal gyrus; model IV: inferior frontal gyrus). The method described herein allows characterization of cortical modulation across different electrode placements and stimulation parameters. Furthermore, knowledge of anatomical distribution of stimulation-evoked activation targeting cortical regions may help predict efficacy and potential side effects, and therefore can be used to improve the therapeutic effectiveness of individual adjustments in DBS patients.


Flexible contextual modulation of naturalistic texture perception in peripheral vision.
Peripheral vision comprises most of our visual field, and is essential in guiding visual behavior. Its characteristic capabilities and limitations, which distinguish it from foveal vision, have been explained by the most influential theory of peripheral vision as the product of representing the visual input using summary statistics. Despite its success, this account may provide a limited understanding of peripheral vision, because it neglects processes of perceptual grouping and segmentation. To test this hypothesis, we studied how contextual modulation, namely the modulation of the perception of a stimulus by its surrounds, interacts with segmentation in human peripheral vision. We used naturalistic textures, which are directly related to summary-statistics representations. We show that segmentation cues affect contextual modulation, and that this is not captured by our implementation of the summary-statistics model. We then characterize the effects of different texture statistics on contextual modulation, providing guidance for extending the model, as well as for probing neural mechanisms of peripheral vision.


Understanding and improving the quality and reproducibility of Jupyter notebooks.
Jupyter Notebooks have been widely adopted by many different communities, both in science and industry. They support the creation of literate programming documents that combine code, text, and execution results with visualizations and other rich media. The self-documenting aspects and the ability to reproduce results have been touted as significant benefits of notebooks. At the same time, there has been growing criticism that the way in which notebooks are being used leads to unexpected behavior, encourages poor coding practices, and makes it hard to reproduce its results. To better understand good and bad practices used in the development of real notebooks, in prior work we studied 1.4 million notebooks from GitHub. We presented a detailed analysis of their characteristics that impact reproducibility, proposed best practices that can improve the reproducibility, and discussed open challenges that require further research and development. In this paper, we extended the analysis in four different ways to validate the hypothesis uncovered in our original study. First, we separated a group of popular notebooks to check whether notebooks that get more attention have more quality and reproducibility capabilities. Second, we sampled notebooks from the full dataset for an in-depth qualitative analysis of what constitutes the dataset and which features they have. Third, we conducted a more detailed analysis by isolating library dependencies and testing different execution orders. We report how these factors impact the reproducibility rates. Finally, we mined association rules from the notebooks. We discuss patterns we discovered, which provide additional insights into notebook reproducibility. Based on our findings and best practices we proposed, we designed Julynter, a Jupyter Lab extension that identifies potential issues in notebooks and suggests modifications that improve their reproducibility. We evaluate Julynter with a remote user experiment with the goal of assessing Julynter recommendations and usability.


Gastrointestinal bleeding in hospitalized children in the United States.
To investigate the epidemiology of GI bleeding in hospitalized children in the United States. Data were obtained from the Healthcare Cost and Utilization Project Kids' Inpatient Database, Agency for Healthcare Research and Quality for the year 2009. The data were weighted to generate national-level estimates. There were 23,383 pediatric discharges with a diagnosis of GI bleeding accounting for 0.5% of all discharges. Children with a GI bleed compared to those without were more likely to be male (54.5% vs. 45.8%; P < 0.001), older (children ≥11 years; 50.8% vs. 38.7%; P < 0.001), and admitted to a teaching hospital (70.5% vs. 56.4%; P < 0.001). Children 11-15 years of age had the highest incidence of GI bleeding (84.2 per 10,000 discharges) and children less than 1 year of age the lowest (24.4 per 10,000 discharges). The highest incidence of GI bleeding was attributable to cases coded as blood in stool (17.6 per 10,000 discharges) followed by hematemesis (11.2 per 10,000 discharges). Those with a GI bleed had a higher co-morbid burden (12.3% vs. 2.3%; P < 0.001) and severity of illness (40.1% vs. 14.5%; P < 0.001). The highest mortality rates associated with GI bleeding were observed in cases with intestinal perforation (8.7%) and esophageal perforation (8.4%). GI bleeding was independently associated with a higher risk of mortality (aOR 1.68, CI 1.53-1.84). Our results describe the epidemiology of GI bleeding in hospitalized children within the United States. We found a substantial risk of mortality attributable to GI bleeding in this patient population. Our study is limited by the exclusion of non-hospitalized children, the reliance on ICD-9-CM codes and the absence of longitudinal follow up of patients.


Development and evaluation of an intervention on suPpoRting infOrmal cAregivers of older people with early CogniTIVe declinE (PROACTIVE): a study protocol based on the Medical Research Council framework.
Caring for people with cognitive problems can have an impact on informal caregivers' health and well-being, and especially increases pressure on healthcare systems due to an increasing ageing society. In response to a higher demand of informal care, evidence suggests that timely support for informal caregivers is essential. The New York University Caregiver Intervention (NYUCI) has proven consistent effectiveness and high adaptability over 30 years. This study has three main objectives: to develop and evaluate the Flemish adaptation of the NYUCI in the context of caregiving for older people with early cognitive decline; to explore the causal mechanism of changes in caregivers' health and well-being and to evaluate the validity and feasibility of the interRAI Family Carer Needs Assessment in Flanders. Guided by Medical Research Council framework, this study covers the development and evaluation phases of the adapted NYUCI, named PROACTIVE-suPpoRting infOrmal cAregivers of older people with early CogniTIVe declinE. In the development phase, we will identify the evidence base and prominent theory, and develop the PROACTIVE intervention in the Flemish context. In the evaluation phase, we will evaluate the PROACTIVE intervention with a pretest and posttest design in 1 year. Quantitative data will be collected with the BelRAI Screener, the BelRAI Social Supplement and the interRAI Family Carer Needs Assessment at baseline and follow-up points (at 4, 8 and 12 months). Qualitative data will be collected using counselling logs, evaluation forms and focus groups. Quantitative data and qualitative data will be analysed with SAS 9.4 software and NVivo software, respectively. Efficacy and process evaluation of the intervention will be performed. This study has been approved by the Ethics Committee of KU Leuven with a dossier number G-2020-1771-R2(MAR). Findings will be disseminated through community information sessions, peer-reviewed publications and national and international conference presentations.


Chemotherapy of trypanosomiasis: the potentiation of antimonial compounds by difluoromethylornithine (DFMO).
The currently available anti-leishmanial antimonial drugs, together with other antimony compounds were individually tested, in combination with difluoromethylornithine (DFMO), against experimental murine trypanosomiasis with central nervous system involvement. Satisfactory cure rates could be achieved using a combination treatment of DFMO with most of these anti-leishmanial drugs, but in general, only when they were administered at least twice daily. Of the compounds tested, the most effective was antimony dimercaptosuccinate (Astiban).


Unraveling Anisotropy in Crystalline Orientation under Shock-Induced Dynamic Responses in High-Entropy Alloy Co25Ni25Fe25Al7.5Cu17.5.
Shock-induced plastic deformation and spall damage in the single-crystalline FCC Co25Ni25Fe25Al7.5Cu17.5 high-entropy alloy (HEA) under varying shock intensities were systematically investigated using large-scale molecular dynamics simulations. The study reveals the significant influence of crystalline orientation on the deformation mechanism and spall damage. Specifically, the shock wave velocities in the [110] and [111] directions are significantly higher than that in the [001] direction, resulting in a two-zone elastic-plastic shock wave structure observed in the [110] and [111] samples, while only a single-wave structure is found in the [001] sample. The plastic deformation is dominated by the FCC to BCC transformation following the Bain path and a small amount of stacking faults during the compression stage in the [001] sample, whereas it depends on the stacking faults induced by Shockley dislocation motion in the [110] and [111] samples. The stacking faults and phase transformation in the [001] sample exhibit high reversibility under release effects, while extensive dislocations are present in the [110] and [111] samples after release. Interestingly, tension-strain-induced FCC to BCC phase transformation is observed in the [001] sample during the release stage, resulting in increased spall strength compared to the [110] and [111] samples. The spall strength estimated from both bulk and free surface velocity history shows reasonable consistency. Additionally, the spall strength remains stable with increasing shock intensities. The study discusses in detail the shock wave propagation, microstructure change, and spall damage evolution. Overall, our comprehensive studies provide deep insights into the deformation and fracture mechanisms of Co25Ni25Fe25Al7.5Cu17.5 HEA under shock loading, contributing to a better understanding of dynamic deformation under extreme environments.


Transcription Factors Drive Opposite Relationships between Gene Age and Tissue Specificity in Male and Female Drosophila Gonads.
Evolutionarily young genes are usually preferentially expressed in the testis across species. Although it is known that older genes are generally more broadly expressed than younger genes, the properties that shaped this pattern are unknown. Older genes may gain expression across other tissues uniformly, or faster in certain tissues than others. Using Drosophila gene expression data, we confirmed previous findings that younger genes are disproportionately testis biased and older genes are disproportionately ovary biased. We found that the relationship between gene age and expression is stronger in the ovary than any other tissue and weakest in testis. We performed ATAC-seq on Drosophila testis and found that although genes of all ages are more likely to have open promoter chromatin in testis than in ovary, promoter chromatin alone does not explain the ovary bias of older genes. Instead, we found that upstream transcription factor (TF) expression is highly predictive of gene expression in ovary but not in testis. In the ovary, TF expression is more predictive of gene expression than open promoter chromatin, whereas testis gene expression is similarly influenced by both TF expression and open promoter chromatin. We propose that the testis is uniquely able to express younger genes controlled by relatively few TFs, whereas older genes with more TF partners are broadly expressed with peak expression most likely in the ovary. The testis allows widespread baseline expression that is relatively unresponsive to regulatory changes, whereas the ovary transcriptome is more responsive to trans-regulation and has a higher ceiling for gene expression.


Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California.
California uses a unique method to screen newborns for cystic fibrosis (CF) that includes gene scanning and DNA sequencing after only one California-40 cystic fibrosis transmembrane conductance regulator (CFTR) panel mutation has been identified in hypertrypsinogenemic specimens. Newborns found by sequencing to have one or more additional mutations or variants (including novel variants) in the CFTR gene are systematically followed, allowing for prospective assessment of the pathogenic potential of these variants. During the first 3 years of screening, 55 novel variants were identified. Six of these novel variants were discovered in five screen-negative participants and three were identified in multiple unrelated participants. Ten novel variants (c.2554_2555insT, p.F1107L, c.-152G>C, p.L323P, p.L32M, c.2883_2886dupGTCA, c.2349_2350insT, p.K114del, c.-602A>T, and c.2822delT) were associated with a CF phenotype (42% of participants were diagnosed at 4 to 25 months of age), whereas 26 were associated with CFTR-related metabolic syndrome to date. Associations with the remaining novel variants were confounded by the presence of other diseases or other mutations in cis or by inadequate follow-up. These findings have implications for how CF newborn screening and follow-up is conducted and will help guide which genotypes should, and which should not, be considered screen positive for CF in California and elsewhere.


Insulin-like growth factor-I induces reactive oxygen species production and cell migration through Nox4 and Rac1 in vascular smooth muscle cells.
We showed previously that insulin-like growth factor-I (IGF-I)-induced vascular smooth muscle cells (VSMCs) proliferation through the production of reactive oxygen species (ROS). However, how IGF-I-induced ROS was unknown. The aim of this study is to investigate the mechanisms by which IGF-I induces ROS production in VSMCs. Methods results Reverse transcription-PCR, real-time PCR, immunoblotting, and confocal microscopic image analysis were employed to determine protein expression, small Rho-GTPase Rac1 activation, and ROS production. Inhibition of NADPH oxidase 4 (Nox4) or Rac1 was performed by means of siRNA technology. Inhibition of Rac1 activity was accomplished using dominant-negative form of Rac1 (N17Rac1) plasmid. VSMCs from Sprague-Dawley rat thoracic aortas were used in this work.IGF-I enhanced ROS production in rat VSMCs. IGF-I increased the protein level of Nox4 but had little effect on its mRNA level. IGF-I induced the activation of Rac1. Either knockdown of Nox4 or inactivation of Rac1 impaired IGF-I-induced ROS. Over-expression of Nox4 increased NADPH oxidase activity, which was not influenced by inactivation of Rac1. Neither over-expression nor knockdown of Rac1 influenced Nox4 expression. Knockdown of Nox4 did not affect IGF-I-induced activation of Rac1. IGF-I increased matrix metalloproteinase (MMP)-2 and 9 activity and promoted VSMC migration, which was inhibited by knockdown of Nox4 and inactivation of Rac1. Our results suggest that Nox4 and Rac1 mediate IGF-I-induced ROS production and cell migration in VSMCs and that Nox4 is not regulated by Rac1.


Comparison between a quantum annealer and a classical approximation algorithm for computing the ground state of an Ising spin glass.
Finding the ground state of an Ising spin glass on general graphs belongs to the class of NP-hard problems, widely believed to have no efficient polynomial-time algorithms to solve them. An approach developed in computer science for dealing with such problems is to devise approximation algorithms; these are algorithms, whose run time scales polynomially with the input size, that provide solutions with provable guarantees on their quality in terms of the optimal unknown solution. Recently, several algorithms for the Ising spin-glass problem on a bounded degree graph that provide different approximation guarantees were introduced. D-Wave, a Canadian-based company, has constructed a physical realization of a quantum annealer and has enabled researchers and practitioners to access it via their cloud service. D-Wave is particularly suited for computing an approximation for the ground state of an Ising spin glass on its Chimera and Pegasus graphs-both with a bounded degree. To assess the quality of D-Wave's solution, it is natural to compare it to classical approximation algorithms specifically designed to solve the same problem. In this work, we compare the performance of a recently developed approximation algorithm to solve the Ising spin-glass problem on graphs of bounded degree against the performance of the D-Wave computer. We also compared the performance of D-Wave's computer in the Chimera architecture against the performance of a heuristic tailored specifically to handle the Chimera graph. We found that the D-Wave computer was able to find better approximations for all the random instances of the problem we studied-Gaussian weights, uniform weights, and discrete binary weights. Furthermore, the convergence times of D-Wave's computer were also significantly better. These results indicate the merit of D-Wave's computer under certain specific instances. More broadly, our method is relevant to a wider class of performance comparison studies, and we suggest that it is important to compare the performance of quantum computers not only against exact classical algorithms with exponential run-time scaling, but also against approximation algorithms with polynomial run-time scaling and a provable guarantee of performance.


Psychiatric morbidity in mothers attending maternal and child health clinics in Abeokuta, Nigeria.
The prevalence rate for psychiatric morbidity in post-partum women attending two maternal and child health clinics in Abeokuta was found to be 6.1%. The cases and the non-cases as determined by a two-stage screening of psychopathology and clinical interview showed that anxiety states and depressive neurosis were the main psychiatric disorders amongst the cohort. In the comparison of various sociodemographic and obstetric variable between the two sub-groups, single (unmarried) status was found to be the only differentiating variable. The low prevalence of psychiatric morbidity was explained in the context of the socio-cultural and emotional implications of childbirth and mothering in the post-natal period in this environment.


Mean ionic activity coefficients in aqueous NaCl solutions from molecular dynamics simulations.
The mean ionic activity coefficients of aqueous NaCl solutions of varying concentrations at 298.15 K and 1 bar have been obtained from molecular dynamics simulations by gradually turning on the interactions of an ion pair inserted into the solution. Several common non-polarizable water and ion models have been used in the simulations. Gibbs-Duhem equation calculations of the thermodynamic activity of water are used to confirm the thermodynamic consistency of the mean ionic activity coefficients. While the majority of model combinations predict the correct trends in mean ionic activity coefficients, they overestimate their values at high salt concentrations. The solubility predictions also suffer from inaccuracies, with all models underpredicting the experimental values, some by large factors. These results point to the need for further ion and water model development.


Early referral of patients with suspected polymyalgia rheumatica - A systematic review.
Prompt diagnosis and treatment of polymyalgia rheumatica (PMR) is crucial to prevent long-term complications and improve patient outcomes. However, there is currently no standardized approach to referral of suspected PMR patients to rheumatologists, leading to inconsistent management practices. The objective of this systematic review was to clarify the existing evidence regarding the following aspects of early management strategies in patients with suspected PMR: diagnostic strategies, GCA screening, glucocorticoid initiation prior to referral, value of shared care and value of fast track clinic. Two authors performed a systematic literature search, data extraction and risk of bias assessment independently. The literature search was conducted in Embase, MEDLINE (PubMed) and Cochrane. Studies were included if they contained cohorts of suspected PMR patients and evaluated the efficacy of different diagnostic strategies for PMR, screening for giant cell arteritis (GCA), starting glucocorticoids before referral to secondary care, shared care, or fast-track clinics. From 2,437 records excluding duplicates, 14 studies met the inclusion criteria. Among these, 10 studies investigated the diagnostic accuracy of various diagnostic strategies with the majority evaluating different clinical approaches, but none of them showed consistently high performance. However, 4 studies on shared care and fast-track clinics showed promising results, including reduced hospitalization rates, lower starting doses of glucocorticoids, and faster PMR diagnosis. This review emphasizes the sparse evidence of early management and referral strategies for patients with suspected PMR. Additionally, screening and diagnostic strategies for differentiating PMR from other diseases, including concurrent GCA, require clarification. Fast-track clinics may have potential to aid patients with PMR in the future, but studies will be needed to determine the appropriate pre-referral work-up.


[Covid-19 and clinical-epidemiological research in Italy: proposal of a research agenda on priority topics by the Italian association of epidemiology].
the Covid-19 pandemic has provoked a huge of clinical and epidemiological research initiatives, especially in the most involved countries. However, this very large effort was characterized by several methodological weaknesses, both in the field of discovering effective treatments (with too many small and uncontrolled trials) and in the field of identifying preventable risks and prognostic factors (with too few large, representative and well-designed cohorts or case-control studies). in response to the fragmented and uncoordinated research production on Covid-19, the italian Association of Epidemiology (AIE) stimulated the formation of a working group (WG) with the aims of identifying the most important gaps in knowledge and to propose a structured research agenda of clinical and epidemiological studies considered at high priority on Covid-19, including recommendations on the preferable methodology. the WG was composed by 25 subjects, mainly epidemiologists, statisticians, and other experts in specific fields, who have voluntarily agreed to the proposal. The agreement on a list of main research questions and on the structure of the specific documents to be produced were defined through few meetings and cycles of document exchanges. twelve main research questions on Covid-19 were identified, covering aetiology, prognosis, interventions, follow-up and impact on general and specific populations (children, pregnant women). For each of them, a two-page form was developed, structured in: background, main topics, methods (with recommendations on preferred study design and warnings for bias prevention) and an essential bibliography. this research agenda represents an initial contribution to direct clinical and epidemiological research efforts on high priority topics with a focus on methodological aspects. Further development and refinements of this agenda by Public Health Authorities are encouraged.


Melanotransferrin is efficiently sorted on the surface of exosomes secreted by melanoma cells.
Cutaneous melanoma is the most lethal type of skin cancer. Early detection is crucial to improve the outcome of melanoma patients. The identification of noninvasive prognostic biomarkers for the follow-up of melanoma patients is still in demand for clinical use. We show here that exosomal melanotransferrin fulfills the biomarker characteristics required to meet this demand. Melanotransferrin is typically overexpressed in melanoma cells compared to other cell types - including cancer cells - and is efficiently sorted and secreted with nanovesicles, or so-called exosomes, due to its membrane-anchoring by a glycosylphosphatidylinositol. Melanotransferrin is exposed on the surface of exosomes and is accessible for antibody recognition. An ELISA was set up to quantify melanotransferrin after immobilization of nanovesicles through the exosomal constituent tetraspanins CD63. Melanotransferrin was detected using a low number of exosomes purified from melanoma cell line cultures, and melanotransferrin detection was abolished by phosphatidylinositol-specific phospholipase C treatment. This exosomal melanotransferrin ELISA was able to discriminate an equal number of assayed exosomes purified from two different melanoma cell lines (A-375 vs. SK-MEL-28). Moreover, plasma samples from patients with melanoma and noncancer disease were assayed using this ELISA and elevated levels of exosomal melanotransferrin were seen in the plasma of patients with melanoma. We propose that exosomal melanotransferrin should be assessed as a potential melanoma biomarker.


Inferring transcriptional compensation interactions in yeast via stepwise structure equation modeling.
With the abundant information produced by microarray technology, various approaches have been proposed to infer transcriptional regulatory networks. However, few approaches have studied subtle and indirect interaction such as genetic compensation, the existence of which is widely recognized although its mechanism has yet to be clarified. Furthermore, when inferring gene networks most models include only observed variables whereas latent factors, such as proteins and mRNA degradation that are not measured by microarrays, do participate in networks in reality. Motivated by inferring transcriptional compensation (TC) interactions in yeast, a stepwise structural equation modeling algorithm (SSEM) is developed. In addition to observed variables, SSEM also incorporates hidden variables to capture interactions (or regulations) from latent factors. Simulated gene networks are used to determine with which of six possible model selection criteria (MSC) SSEM works best. SSEM with Bayesian information criterion (BIC) results in the highest true positive rates, the largest percentage of correctly predicted interactions from all existing interactions, and the highest true negative (non-existing interactions) rates. Next, we apply SSEM using real microarray data to infer TC interactions among (1) small groups of genes that are synthetic sick or lethal (SSL) to SGS1, and (2) a group of SSL pairs of 51 yeast genes involved in DNA synthesis and repair that are of interest. For (1), SSEM with BIC is shown to outperform three Bayesian network algorithms and a multivariate autoregressive model, checked against the results of qRT-PCR experiments. The predictions for (2) are shown to coincide with several known pathways of Sgs1 and its partners that are involved in DNA replication, recombination and repair. In addition, experimentally testable interactions of Rad27 are predicted. SSEM is a useful tool for inferring genetic networks, and the results reinforce the possibility of predicting pathways of protein complexes via genetic interactions.


Food and drinking water hygiene and intestinal protozoa in deployed German soldiers.
This report analyzes the occurrence of Cryptosporidium spp., E. histolytica, and G. intestinalis in stool of returnees from military deployments and the impact of hygiene precautions. Between 2007 and 2010, stool samples of 830 returnees that were obtained 8-12 weeks after military deployments in Afghanistan, Uzbekistan, the Balkans, Democratic Republic of the Congo/Gabonese Republic, and Sudan and 292 control samples from non-deployed soldiers were analyzed by PCR for Cryptosporidium spp., E. histolytica, G. intestinalis, and the commensal indicator of fecal contamination E. dispar. Data on hygiene precautions were available. The soldiers were questioned regarding gastrointestinal and general symptoms. Among 1122 stool samples, 18 were positive for G. intestinalis, 10 for E. dispar, and no-one for Cryptosporidium spp. and E. histolytica. An increased risk of acquiring chronic parasitic infections in comparison with non-deployed controls was demonstrated only for G. intestinalis in Sudan, where standardized food and drinking water hygiene precautions could not be implemented. Standard food and drinking water hygiene precautions in the context of screened military field camps proved to be highly reliable in preventing food-borne and water-borne chronic infections and colonization by intestinal protozoa, leading to detection proportions similar to those in non-deployed controls.


Standardisation of the factor H autoantibody assay.
The screening of all atypical haemolytic uraemic syndrome (aHUS) patients for factor H autoantibodies is best practice. However, there is no consensus assay for the reporting of factor H autoantibody titres. In this study, three European complement laboratories with expertise in the field of autoantibody testing address this by systematically evaluating several ELISA methods used for the detection of factor H autoantibodies. All methods tested adequately detect high titre samples. However, this study recommends the Paris method for the detection and reporting of factor H autoantibodies to be used when setting up a factor H autoantibody screen. The importance of individual sample background subtraction in these ELISA tests was established. The use of a relative or arbitrary unit index with a common positive and negative serum allowed for consistent comparison of findings from different test centres. Therefore, it is recommended that a standard arbitrary unit scale based on a titration curve from a common positive anti-serum be adopted to allow future establishment of the relative importance of particular titres of factor H autoantibodies in aHUS. Systematic assay for the presence of factor H autoantibodies in patients using the Paris method will provide the longitudinal analysis needed to fully establish the importance of factor H autoantibodies in disease. This will feed into additional research to clarify whether additional factors have a bearing on the phenotype/outcome of autoimmune aHUS.


Analysis of the static properties of cluster formations in symmetric linear multiblock copolymers.
We use molecular dynamics simulations to study the static properties of a single linear multiblock copolymer chain under poor solvent conditions varying the block length N, the number of blocks n, and the solvent quality by variation of the temperature T. We study the most symmetrical case, where the number of blocks of monomers of type A, n(A), equals that of monomers B, n(B) (n(A) = n(B) = n/2), the length of all blocks is the same irrespective of their type, and the potential parameters are also chosen symmetrically, as for a standard Lennard-Jones fluid. Under poor solvent conditions the chains collapse and blocks with monomers of the same type form clusters, which are phase separated from the clusters with monomers of the other type. We study the dependence of the size of the clusters formed on n, N and T. Furthermore, we discuss our results with respect to recent simulation data on the phase behaviour of such macromolecules, providing a complete picture for the cluster formations in single multiblock copolymer chains under poor solvent conditions.


Redefining and redesigning hospital discharge to enhance patient care: a randomized controlled study.
Patients are routinely ill-prepared for the transition from hospital to home. Inadequate communication between Hospitalists and primary care providers can further compromise post-discharge care. Redesigning the discharge process may improve the continuity and the quality of patient care. To evaluate a low-cost intervention designed to promptly reconnect patients to their "medical home" after hospital discharge. Randomized controlled study. Intervention patients received a "user-friendly" Patient Discharge Form, and upon arrival at home, a telephone outreach from a nurse at their primary care site. A culturally and linguistically diverse group of patients admitted to a small community teaching hospital. Four undesirable outcomes were measured after hospital discharge: (1) no outpatient follow-up within 21 days; (2) readmission within 31 days; (3) emergency department visit within 31 days; and (4) failure by the primary care provider to complete an outpatient workup recommended by the hospital doctors. Outcomes of the intervention group were compared to concurrent and historical controls. Only 25.5% of intervention patients had 1 or more undesirable outcomes compared to 55.1% of the concurrent and 55.0% of the historical controls. Notably, only 14.9% of the intervention patients failed to follow-up within 21 days compared to 40.8% of the concurrent and 35.0% of the historical controls. Only 11.5% of recommended outpatient workups in the intervention group were incomplete versus 31.3% in the concurrent and 31.0% in the historical controls. A low-cost discharge-transfer intervention may improve the rates of outpatient follow-up and of completed workups after hospital discharge.


Cross-talk between TGF-beta1 and IL-6 in human trabecular meshwork cells.
To investigate the relationship between transforming growth factor beta-1 (TGF-beta1) and interleukin-6 (IL-6) in human trabecular meshwork (HTM) cells as well as to identify the signaling pathway/s involved in the increased IL-6 expression that occurs in response to mechanical stress and TGF-beta1. All experiments were performed in confluent monolayers of HTM cells at passage 3. Secreted IL-6 was quantified by ELISA. Levels of IL-6 mRNA were evaluated by polymerase chain reaction (PCR) analysis. Activation of the IL-6 and TGF-beta1 promoters was monitored by measuring secreted alkaline phosphatase protein (SEAP) released into the culture medium by HTM cells infected with an adenovirus expressing the SEAP reporter gene that was controlled by either the IL-6 promoter (AdIL6-SEAP) or the TGF-beta1 promoter (AdTGFbeta1-SEAP). Cyclic mechanical stress (5% elongation, one cycle per second) was applied using the Flexcell System. Reagents used in this study included human TGF-beta1, human IL-6, and the inhibitors for the p38 mitogen-activated protein kinase (MAPK; SB202190), c-jun NH2-terminal kinase (JNK; SP600125), extracellular-regulating kinase (ERK; PD98059), and TGF type I activin receptor (SB431542). Incubation of HTM cells with TGF-beta1 (5 ng/ml) resulted in a significant increase in the protein and mRNA levels of IL-6, which was significantly diminished in the presence of the inhibitors for p38 MAPK or JNK. No transcriptional activation of the exogenous IL-6 promoter was observed following TGF-beta1 treatment. In addition, the presence of inhibitors for the p38 MAPK, ERK, and TGF-beta1 pathways significantly decreased the increased expression of IL-6 by cyclic mechanical stress. Furthermore, exposure of HTM cells to IL-6 (100 ng/ml) demonstrated the transcriptional activation of TGF-beta1 promoter, which was severely impaired by blocking the p38 MAPK pathway. Our results indicate that TGF-beta1 participates in the regulation of basal expression and the stretch-induced expression of IL-6 and suggest the possible existence in cultured HTM cells of an autocrine loop between IL-6 and TGF-beta1. We also found that p38 MAPK might play a contributing role in the maintenance of such a loop.


Genome-Wide Identification of R2R3-MYB Genes and Expression Analyses During Abiotic Stress in Gossypium raimondii.
The R2R3-MYB is one of the largest families of transcription factors, which have been implicated in multiple biological processes. There is great diversity in the number of R2R3-MYB genes in different plants. However, there is no report on genome-wide characterization of this gene family in cotton. In the present study, a total of 205 putative R2R3-MYB genes were identified in cotton D genome (Gossypium raimondii), that are much larger than that found in other cash crops with fully sequenced genomes. These GrMYBs were classified into 13 groups with the R2R3-MYB genes from Arabidopsis and rice. The amino acid motifs and phylogenetic tree were predicted and analyzed. The sequences of GrMYBs were distributed across 13 chromosomes at various densities. The results showed that the expansion of the G. Raimondii R2R3-MYB family was mainly attributable to whole genome duplication and segmental duplication. Moreover, the expression pattern of 52 selected GrMYBs and 46 GaMYBs were tested in roots and leaves under different abiotic stress conditions. The results revealed that the MYB genes in cotton were differentially expressed under salt and drought stress treatment. Our results will be useful for determining the precise role of the MYB genes during stress responses with crop improvement.


Protecting Unrooted Cuttings From Bemisia tabaci (Hemiptera Aleyrodidae) During Propagation.
In North America, the sweetpotato whitefly, Bemisia tabaci Genn., is an important pest of greenhouse poinsettia. Growers have limited options to control this pest during propagation of cuttings, which are rooted under mist for several weeks. Early establishment of this pest increases the difficulty of managing the whitefly and retaining high aesthetic standard during the remaining crop production phase. We evaluated two neonicotinoids with translaminar activity, thiamethoxam (Flagship 25WG), and acetamiprid (TriStar 70 WSP), for control of B. tabaci pre-infested on unrooted cuttings propagated under mist. In an experimental greenhouse, both materials significantly reduced whitefly populations, providing an average reduction of 87.8% and 61.5% total recovered whitefly stages respectively, compared with controls. In another test, dipping cuttings in thiamethoxam (immersion treatment) did not improve control significantly, when compared with foliar sprays applied at label rate. In a commercial greenhouse operation, immersion treatments of thiamethoxam on pre-infested poinsettia cuttings maintained whiteflies at ≤ 0.02/plant, compared with up to 0.33/plant in untreated cuttings. Our data suggest that treating unrooted cuttings before or at the start of propagation can be part of an overall strategy for growers to manage whiteflies in poinsettia production.


A Digital RNA Signature of Circulating Tumor Cells Predicting Early Therapeutic Response in Localized and Metastatic Breast Cancer.
The multiplicity of new therapies for breast cancer presents a challenge for treatment selection. We describe a 17-gene digital signature of breast circulating tumor cell (CTC)-derived transcripts enriched from blood, enabling high-sensitivity early monitoring of response. In a prospective cohort of localized breast cancer, an elevated CTC score after three cycles of neoadjuvant therapy is associated with residual disease at surgery (P = 0.047). In a second prospective cohort with metastatic breast cancer, baseline CTC score correlates with overall survival (P = 0.02), as does persistent CTC signal after 4 weeks of treatment (P = 0.01). In the subset with estrogen receptor (ER)-positive disease, failure to suppress ER signaling within CTCs after 3 weeks of endocrine therapy predicts early progression (P = 0.008). Drug-refractory ER signaling within CTCs overlaps partially with presence of ESR1 mutations, pointing to diverse mechanisms of acquired endocrine drug resistance. Thus, CTC-derived digital RNA signatures enable noninvasive pharmacodynamic measurements to inform therapy in breast cancer.Significance: Digital analysis of RNA from CTCs interrogates treatment responses of both localized and metastatic breast cancer. Quantifying CTC-derived ER signaling during treatment identifies patients failing to respond to ER suppression despite having functional ESR1. Thus, noninvasive scoring of CTC-RNA signatures may help guide therapeutic choices in localized and advanced breast cancer. Cancer Discov; 8(10); 1286-99. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195.


Averroës in The school of Athens: a Renaissance man and his contribution to Western thought and neuroscience.
The European Renaissance was a revolutionary movement in human history. In this era of the rebirth of humanity, a great number of valuable artworks were created. One of these masterpieces is the magnificent wall painting The School of Athens, by Raphael, which is also known as a "visualization of knowledge." Raphael depicted almost all ancient Greek philosophers in this fresco. The painting displays one noticeable figure among the scholars: the philosopher/scientist Averroës from Andalusia. Western thought was greatly influenced by Averroës' philosophy. Averroës was as extraordinary a physician as he was a philosopher. His medical works presented novel concepts such as the discovery of the photoreceptor function of the retina, describing symptoms and signs of Parkinson's disease, and proposing a cardiac/vascular origin of cerebral stroke. In this article, we aimed to introduce Averroës' works and his contribution to neuroscience in the context of art, framed particularly with Raphael's masterwork The School of Athens.


[Diabetes in hemodialysis: study of differential factors].
In uremic patients with diabetes mellitus, morbi-mortality on maintenance hemodialysis is considerably higher than in nondiabetic patients. This is mainly due to age, seniority and quality of the hemodialysis therapy, nutritional status, plasmatic lipid levels and associated pathology. We compare all these factors in the uremic patients under hemodialysis in diabetics and non-diabetics. We have studied 307 uremic patients under hemodialysis therapy during 199 and 1996. Sixty of them had been diagnosticated of diabetes mellitus (19.6%), 17 were type I (DM-I) and 27 were type II (DM-II). We selected two control groups no-diabetics, one for each subgroup of diabetics with similar characteristics in age, sex and hemodialysis seniority. The control group for DM-I were 34 patients and for DM-II were 54 patients. Ideal body weight percentage, body mass index, mid-arm muscle circumference percentil, serum albumin and prealbumin are subnormal for DM-I. By considering whole nutritional date, a moderate to severe malnutrition was observed in 79% of DM-I patients, 50.4% of all non diabetics and only in 30.6% of patients included in the DM-II group. However, DM-II patients present hypertrigliceridemia and a decrease in HDL cholesterol and apolipoprotein A levels with a high atherogenic index. Significantly higher rates of associated pathology were observed among both types of diabetic patients than their control groups and especially referred to cardiovascular and neurological diseases. In conclusion, diabetes mellitus is an increasing incidence pathology in hemodialysis programs, that is associated to a higher morbi-mortality because vascular disease. Undernutrition is the main factor in DM-II whereas hyperlipidemia is in DM-II.


Intrathecal therapy for the management of cancer pain.
Inadequately managed cancer pain continues to be a significant problem despite increased awareness, improved knowledge and understanding of pain pathophysiology, and standardized treatment guidelines of this distressing and debilitating symptom complex. Small subsets of patients who are refractory to optimal medical management because of drug toxicity or unsatisfactory analgesia may be candidates for exteriorized or implantable intrathecal drug delivery systems. By delivering opioids and other agents directly to the central nervous system, intrathecal drug administration can offer superior pain relief with less toxicity at a fraction of the systemic dose. With adjuncts such as local anesthetics and clonidine, intrathecal therapy also allows for broader therapeutic options in the most difficult of cases. In general, intrathecal therapy is underused despite evidence of its efficacy, safety, and cost-effectiveness.


Study Design and Rationale of EXPLORER-HCM: Evaluation of Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy.
Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by unexplained left ventricular (LV) hypertrophy associated with dynamic LV outflow tract obstruction. Current medical therapies are nonspecific and have limited efficacy in relieving symptoms. Mavacamten is a first-in-class targeted inhibitor of cardiac myosin, which has been shown to reduce LV outflow tract obstruction, improve exercise capacity, and relieve symptoms of oHCM in the PIONEER-HCM phase 2 study. EXPLORER-HCM is a multicenter, phase 3, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of mavacamten in treating symptomatic oHCM. Eligible adults with oHCM and New York Heart Association Functional Class II or III are randomized 1:1 to receive once-daily, oral mavacamten, or matching placebo for 30 weeks. The primary composite functional end point is clinical response at week 30 compared to baseline defined as either (1) an increase in peak oxygen consumption ≥1.5 mL/kg/min and reduction of at least one New York Heart Association class; or (2) an improvement of ≥3.0 mL/kg/min in peak oxygen consumption with no worsening of New York Heart Association class. Secondary end points include change in postexercise LV outflow tract gradient, New York Heart Association class, peak oxygen consumption, and patient-reported outcomes assessed by the Kansas City Cardiomyopathy Questionnaire and a novel HCM-specific instrument. Exploratory end points aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology. EXPLORER-HCM is a phase 3 trial in oHCM testing a first-in-class, targeted strategy of myosin inhibition to improve symptom burden and exercise capacity through reducing LV outflow tract obstruction. Results of this trial will provide evidence to support the first disease-specific treatment for HCM. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03470545.


Increased intracranial pressure is associated with elevated cerebrospinal fluid ADH levels in closed-head injury.
Head injury frequently results in increased intracranial pressure and brain edema. Investigators have demonstrated that ischemic injury causes an increase in cerebrospinal fluid (CSF) levels of antidiuretic hormone (ADH); increased CSF ADH levels exacerbate cerebral edema, and inhibition of the ADH system with specific ADH antagonists reduces cerebral edema. The current study was designed to test the hypothesis that elevated levels of ADH are present in the CSF of subjects with head injury. Ventricular CSF and blood samples were taken from 11 subjects with head injury and 12 subjects with no known head trauma or injury. ADH levels were analyzed using radioimmunoassay. Severity of increased intracranial pressure (ICP) was rated in head-injured subjects using a four-point ordinal scale, based on which treatments were necessary to reduce ICP. Subjects with head injury had higher CSF (3.2 versus 1.2 pg/ml; P<0.02) and plasma (4.1 versus 1.4 pg/ml; P<0.02) levels of ADH than did control subjects. In head-injured subjects, CSF ADH levels positively correlated with severity of ICP. The results of this study suggest that ADH plays a role in brain edema associated with closed head injury.


The interactions of dopamine and oxidative damage in the striatum of patients with neurodegenerative diseases.
The striatum with a number of dopamine containing neurons, receiving projections from the substantia nigra and ventral tegmental area; plays a critical role in neurodegenerative diseases of motor and memory function. Additionally, oxidative damage to nucleic acid may be vital in the development of age-associated neurodegeneration. The metabolism of dopamine is recognized as one of the sources of reactive oxygen species through the Fenton mechanism. The proposed interactions of oxidative insults and dopamine in the striatum during the progression of diseases are the hypotheses of most interest to our study. This study investigated the possibility of significant interactions between these molecules that are involved in the late-stage of Alzheimer's disease (AD), Parkinson disease (PD), Parkinson disease dementia, dementia with Lewy bodies, and controls using ELISA assays, autoradiography, and mRNA in situ hybridization assay. Interestingly, lower DNA/RNA oxidative adducts levels in the caudate and putamen of diseased brains were observed with the exception of an increased DNA oxidative product in the caudate of AD brains. Similar changes were found for dopamine concentration and vesicular monoamine transporter 2 densities. We also found that downstream pre-synaptic dopamine D1 Receptor binding correlated with dopamine loss in Lewy body disease groups, and RNA damage and β-site APP cleaving enzyme 1 in the caudate of AD. This is the first demonstration of region-specific alterations of DNA/RNA oxidative damage which cannot be viewed in isolation, but rather in connection with the interrelationship between different neuronal events; chiefly DNA oxidative adducts and density of vesicular monoamine transporter 2 densities in AD and PD patients.


Maturation of the Escherichia coli divisome occurs in two steps.
Cell division proteins FtsZ (FtsA, ZipA, ZapA), FtsE/X, FtsK, FtsQ, FtsL/B, FtsW, PBP3, FtsN and AmiC localize at mid cell in Escherichia coli in an interdependent order as listed. To investigate whether this reflects a time dependent maturation of the divisome, the average cell age at which FtsZ, FtsQ, FtsW, PBP3 and FtsN arrive at their destination was determined by immuno- and GFP-fluorescence microscopy of steady state grown cells at a variety of growth rates. Consistently, a time delay of 14-21 min, depending on the growth rate, between Z-ring formation and the mid cell recruitment of proteins down stream of FtsK was found. We suggest a two-step model for bacterial division in which the Z-ring is involved in the switch from cylindrical to polar peptidoglycan synthesis, whereas the much later localizing cell division proteins are responsible for the modification of the envelope shape into that of two new poles.