Role of insulin-like growth factor-I in esophageal mucosal healing processes.
The current study examines the stimulation of healing processes and signal transduction that is mediated by insulin-like growth factor-I (IGF-I) in an ex vivo esophageal explant model when using tyrphostin inhibition of receptor tyrosine kinase. The explant model provides a 3-dimensional cellular environment of multiple interacting cells isolated from the neural and vascular supply. Tyrphostins previously characterized for their interactions with epithelial growth factor (EGF) receptor-associated protein tyrosine kinases were tested for their potential effects on IGF-I growth-promoting activity. Explants of rabbit esophagus were incubated in media with or without IGF-I. Tyrphostins 1, 23, 25, 46, 47, 51, and 63 were added. We assessed DNA synthesis by tritiated thymidine incorporation. Outgrowth from the edge of the primary mucosa of the explant was evaluated on histologic sections, and cell proliferation was confirmed with immunohistology. IGF-I increased the incorporation of tritiated thymidine by 50% to 100%. Tyrphostins 23 and 47 eliminated IGF-I-induced proliferation in a dose-dependent manner. Tyrphostins 25, 46, and 51--along with negative controls tyrphostin 1 and tyrphostin 63--were ineffective, inasmuch as IGF-I-stimulated growth remained unchanged in their presence. Proliferative activity demonstrated by PCNA staining was confined to new mucosa. Two of 5 tyrphostins originally developed as EGF receptor protein tyrosine kinase inhibitors were effective in inhibiting the actions of exogenous IGF-I. We conclude that IGF-I stimulation may play an important role in repair processes in the esophagus and that this stimulation can be inhibited by using specific tyrphostins.


Best practices in the flow cytometry of microalgae.
Microalgae are photosynthetic microorganisms with a major influence on global ecosystems. Further, owing to the production of various secondary metabolites, microalgae are also intensively studied for their enormous potential in biotechnology and its applications. While flow cytometry (FCM) is a fast and reliable method particularly suitable for genome size estimation in plant and animal studies, its application to microalgae often comes with many methodological challenges due to specific issues (e.g., cell wall composition, and presence of various secondary metabolites). Sample preparation requires considerable amounts of biomass, chemical fixation, and/or extraction of cellular components. In genome size estimation, appropriate methods for isolation of intact nuclei (using lysis buffers, razor-blade chopping, various enzymes, or bead-beating of cells) are essential for successful and high-quality analyses. Nuclear DNA amounts of microalgae diverge greatly, varying by almost 30,000-fold (0.01 to 286 pg). Even though new algal reference standards for genome size are now being introduced, animal red blood cells and nuclei from plant tissues are still predominantly used. Due to our limited knowledge of microalgal life cycles, particular caution should be taken during 1C/2C-value (or ploidy level) assignments.


Dependence of electrical properties on thermal temperature in nanocrystalline SnO2 thin films.
Nanocrystalline SnO2 thin films were prepared by pulsed laser deposition techniques on clean glass substrates, and the films were then annealed for 30 min from 50 to 550 degrees C with a step of 50 degrees C, respectively. The investigation of X-ray diffraction confirmed that the various SnO2 thin films were consisted of nanoparticles with average grain size in the range of 23.7-28.9 nm. Root-mean-square surface roughness of the as-prepared SnO2 thin film was measured to be 25.6 nm which decreases to 16.2 nm with thermal annealing. Electrical resistivity and refractive index were measured as a function of annealing temperature, and found to lie between 1.24 to 1.45 momega-cm, and 1.502 to 1.349, respectively. The results indicate that nearly opposite actions to root-mean-square surface roughness and electrical resistivity make a unique performance with thermal annealing temperature. The post annealing shows greater tendency to affect the structural and electrical properties of SnO2 thin films which composed of nanoparticles.


Coiling of very large or giant cerebral aneurysms: long-term clinical and serial angiographic results.
Initial complete occlusion of very large or giant aneurysms often cannot be accomplished, and most will partially reopen over time. This study was performed to assess the clinical and angiographic outcome of patients with very large or giant cerebral aneurysms treated with detachable coils. During 6 years, 29 patients with 31 very large or giant (20-55-mm) cerebral aneurysms were initially treated with detachable coils. Nineteen patients presented with subarachnoid hemorrhage (SAH), and eight patients had symptoms of mass effect. One patient had an incidental aneurysm, and one patient had an additional aneurysm. Twenty-three (79%) of 29 patients had a good clinical outcome at a median follow-up of 50 months. One of 19 patients presenting with SAH had repeat bleed (annual rebleeding rate, 1.45%). After initial coiling, seven of 31 aneurysms were incompletely occluded; this rate increased to 20 of 29 aneurysms at 6-month follow-up angiography. After 16 repeat coiling procedures in 13 aneurysms, 12 of 29 aneurysms in surviving patients were still incompletely occluded. After additional treatment other than coiling (parent-vessel occlusion and/or surgery) in eight aneurysms, three of 25 aneurysms in 24 surviving patients were incompletely occluded. Only 13 (42%) of 31 aneurysms had one coiling as a sole therapy. Coiling of very large or giant aneurysms can be considered. Long-term clinical outcomes were good in 79% of patients. The stability of the coil mesh over time was poor, requiring repeat coiling, surgery, and/or parent-vessel balloon occlusion in 58% of the aneurysms primarily treated with coils.


Icarisid II, a PDE5 inhibitor from Epimedium wanshanense, increases cellular cGMP by enhancing NOS in diabetic ED rats corpus cavernosum tissue.
The aim of this study was to explore the effects and mechanisms of Icarisid II (ICA-II) on enhancing the cellular cGMP in rat corpus cavernosum tissue (RCCT). Diabetes mellitus Wistar rats were induced by streptozotocin, and diabetic ED rats were selected for the RCCT culture by apomorphine. ICA-II was extracted and purified from Icariin (ICA) by enzymatic method. The RCCT was treated with ICA-II, ICA and Sildenafil at different concentrations. cGMP and nitric oxide synthase (NOS) activities were checked respectively by enzyme immunoassay. Meanwhile, nNOS, iNOS and eNOS in RCCT were checked by western blot. ICA-II evaluated the intracellular cGMP to 8.01 ± 1.02 pmol mg(-1) min(-1), which is much weaker than that from Sildenafil (12.4 ± 1.16 pmol mg(-1) min(-1)) (P < 0.05). There is no significant difference between ICA-II and ICA. With the treatment of 10 μm ICA-II for 24 and 48 h, nNOS expression was significantly increased in RCCT (P < 0.05), while the eNOS expression level was very low without any change. Notably, ICA-II increased the intracellular NOS activity significantly in vitro in RCCT. Except the PDE5 inhibitory effect, ICA-II increases the intracellular cGMP through the enhancement of nNOS expression and NOS activity in RCCT in vitro. ICA-II implies a potential compound for neurogenic erectile dysfunction by NO-cGMP pathway.


Atypical manifestations of spinal infections.
Because of alarming delays in the diagnosis and treatment of vertebral osteomyelitis we have reviewed our experience over the past 15 years. Of the 36 cases, 25 were pyogenic and 11 tuberculous. Because of late referral there was a delay from onset of symptoms to diagnosis of at least three months in 13 patients. The reason for this was the failure of the initial physician to consider osteomyelitis in the differential diagnosis of a febrile illness associated with back pain. The majority of our patients from the onset did not have intense localized pain, tenderness and a high fever which is the classical clinical picture in this condition. Seven patients with a long history required surgical exploration and debridement of the lesion in order to eradicate the infection. The remainder did well on 6 to 12 weeks of antibiotic therapy. None required spinal fusion. Ten of 11 patients with spinal tuberculosis had curettage of the lesion and spinal fusion. Patients with diabetes, malignancy, alcoholism, corticosteroid therapy and recent lower urinary tract surgery were found to be at particular risk of developing spinal osteomyelitis. Very often it was difficult to identify differences in the presentation of pyogenic and tuberculous infections.


High resource utilization does not affect mortality in acute respiratory failure patients managed with tracheostomy.
Tracheostomy practice in patients with acute respiratory failure (ARF) varies greatly among institutions. This variability has the potential to be reflected in the resources expended providing care. In various healthcare environments, increased resource expenditure has been associated with a favorable effect on outcome. To examine the association between institutional resource expenditure and mortality in ARF patients managed with tracheostomy. We developed analytic models employing the University Health Systems Consortium (Oakbrook, Illinois) database. Administrative coding data were used to identify patients with the principal diagnosis of ARF, procedures, complications, post-discharge destination, and survival. Mean resource intensity of participating academic medical centers was determined using risk-adjusted estimates of costs. Mortality risk was determined using a multivariable approach that incorporated patient-level demographic and clinical variables and institution-level resource intensity. We analyzed data from 44,124 ARF subjects, 4,776 (10.8%) of whom underwent tracheostomy. Compared to low-resource-intensity settings, treatment in high-resource-intensity academic medical centers was associated with increased risk of mortality (odds ratio 1.11, 95% CI 1.05-1.76), including those managed with tracheostomy (odds ratio high-resource-intensity academic medical center with tracheostomy 1.10, 95% CI 1.04-1.17). We examined the relationship between complication development and outcome. While neither the profile nor number of complications accumulated differed comparing treatment environments (P > .05 for both), mortality for tracheostomy patients experiencing complications was greater in high-resource-intensity (95/313, 30.3%) versus low-resource-intensity (552/2,587, 21.3%) academic medical centers (P < .001). We were unable to demonstrate a positive relationship between resource expenditure and outcome in ARF patients managed with tracheostomy.


The Mixture of Autoregressive Hidden Markov Models of Morphology for Dentritic Spines During Activation Process.
The dendritic spines play a crucial role in learning and memory processes, epileptogenesis, drug addiction, and postinjury recovery. The shape of the dendritic spine is a morphological key to understand learning and memory process. The classification of the dendritic spines is based on their shapes but the major questions are how the shapes changes in time, how the synaptic strength changes, and is there a correlation between shapes and synaptic strength? Because the changes of the classes by dendritic spines during activation are time dependent, the forward-directed autoregressive hidden Markov model (ARHMM) can be used to model these changes. It is also more appropriate to use an ARHMM directed backward in time. Thus, the mixture of forward-directed ARHMM and backward-directed ARHMM (MARHMM) is used to model time-dependent data related to the dendritic spines. In this article, we discuss (1) how to choose the initial probability vector and transition and dependence matrices in ARHMM and MARHMM for modeling the dendritic spines changes and (2) how to estimate these matrices. Many descriptors to classify dendritic spines in two-dimensional or/and three-dimensional (3D) are available. Our results from sensitivity analysis show that the classification that comes from 3D descriptors is closer to the truth, and estimated transition and dependence probability matrices are connected with the molecular mechanism of the dendritic spines activation.


Distraction osteogenesis for tracheostomy dependent children with severe micrognathia.
Obstructive sleep apnea (OSA) in pediatric populations is often associated with congenital craniofacial malformations resulting in decreased pharyngeal airway, which in severe cases leads to tracheostomy dependence. The purpose of this study was to use distraction osteogenesis to improve the airway and decannulate the tracheostomy. This study involved 11 OSA tracheostomy-dependent patients (age range, 4 months to 6 years) who underwent bilateral distraction in the mandibular body using extraoral distraction devices. Following a latency period of 4 days, gradual distraction at a rate of 1 mm/d was performed followed by a consolidation period of 10 weeks. Three-dimensional computed tomography reconstruction of the face and neck before and after the mandibular lengthening aided in quantitative volumetric evaluation of mandibular volume and airway volume. The results demonstrated mandibular elongation of a mean of 30 mm on each side, an increase in mandibular volume by an average of 29.19%, and increase in pharyngeal airway by an average of 70.53%. Two to 3 months following the last lengthening, all 11 patients were decannulated with improvement of signs and symptoms of OSA and elimination of oxygen requirement. Mean follow-up was 2.0 years. The oxygen saturation level rose to more than 95%, and the apnea index respiratory disturbance index was less than 2 episodes per hour for all patients. Bilateral mandibular distraction is a useful method in younger children to decannulate permanent tracheostomy expanding the hypoplastic mandible and concomitantly advance the base of tongue and hyoid bone increasing the pharyngeal airway.


A cost-utility analysis of pregabalin versus duloxetine for the treatment of painful diabetic neuropathy.
The objective of the current study was to determine the cost-utility of pregabalin versus duloxetine for treating painful diabetic neuropathy (PDN) using a decision tree analysis. Literature searches identified clinical trials and real-world studies reporting the efficacy, tolerability, safety, adherence, opioid usage, health care utilization, and costs of pregabalin and duloxetine. The proportions of patients reported in the included studies were used to determine probabilities in the decision tree model. The base-case model included the Food and Drug Administration (FDA)-approved doses of pregabalin (300 mg/day) and duloxetine (60 mg/day), whereas "real-world" sensitivity analyses explored the effects over a range of doses (pregabalin 75-600 mg/day, duloxetine 20-120 mg/day). A 6-month time horizon and a US third-party payer perspective were chosen for the study. Outcomes from the model were expressed as cost per quality-adjusted life-year (QALY). In the base-case model, duloxetine cost less and was more effective than pregabalin (incremental cost -$187, incremental effectiveness 0.011 QALYs). Results from two real-world sensitivity analyses indicated that duloxetine cost $16,300 and $20,667 more per additional QALY than pregabalin. Using a decision tree model that incorporated both clinical trial and real-world data, duloxetine was a more cost-effective option than pregabalin in the treatment of PDN from the perspective of third-party payers.


Accommodation to a reduced islet cell mass in dogs.
The quantitative insulin response to glucose stimulus can be drastically reduced by subtotal pancreatectomy. An 80% pancreatectomy was performed preserving the pancreatic duct in seven dogs. The insulin output into the portal vein and cephalic vein insulin after intravenous glucose challenge were measured. Output was recorded in 25 controls, and before and 2 wk after subtotal pancreatectomy in the seven animals. Histologic sections of the original resection were compared with the remnant of pancreas taken at the end of the study. In this model, which approaches islet cell failure in terms of glucose homeostasis, the tactics that permit enhancement of islet function can be discerned and to some degree quantitated. The pancreatic remnant does not oversecrete to approximate normal function, although glucose sensitivity is somewhat enhanced. No beta-cell hyperplasia was seen. Despite low insulin output into the portal vein, systemic insulin levels are conserved. This decrease in the plasma clearance of insulin supports glucose homeostasis. Accommodation to severe islet reduction occurs via both intrapancreatic and, more importantly, extrapancreatic mechanisms.


Rates of Delayed Postcochlear Implant Pain in the Pediatric Population-Role of Proactive Approach.
To investigate the rates of delayed postoperative cochlear implantation pain (DPCIP) in the pediatric population, using a "reach-out" proactive approach. Secondary aims included the possible impact of surgery extent or the patient ethnicity on DPCIP rates. A cross-sectional study was conducted at Soroka University Medical Center in Israel. Demographics and data regarding the surgery and surgical complications were collected from the medical records of the patients. A telephone questionnaire was conducted for parents of all children who underwent cochlear implantation (CI) between 2007 and 2020. The questions addressed pain at four time periods: during hospitalization after surgery, 3 months, 2 years, and 5 years after surgery. Out of 213 patients, 129 (60%) were included in this study. The mean age was 41 months (±40). Unilateral CI was performed in 72 (56%) patients. At 3 months and 2 years after surgery, 8.5% of patients reported pain (visual analog scale [VAS] ≥ 1). Five years after surgery, a slight increase in the number of patients who reported pain (12%) was observed. Of those experiencing pain 2 years and 5 years after surgery, 10/12 (83%) and 11/16 (69%), respectively, reported a new onset of the pain. Surgery extent and cultural background were not significantly associated with DPCIP rates. No correlations were found between patients complaining of pain and any surgical complications. DPCIP rates may be underrecognized and higher than previously reported, reaching up to 12%. This long-term effect should be acknowledged and discussed with parents upon informed consent.


Resting heart rate control and prognosis in coronary artery disease patients with hypertension previously treated with bisoprolol: a sub-group analysis of the BISO-CAD study.
Resting heart rate (RHR) is considered as a strong predictor of total mortality and hospitalization due to heart failure in hypertension patients. Bisoprolol fumarate, a second-generation beta-adrenoreceptor blockers (β-blocker) is commonly prescribed drug to manage hypertension. The present study was to retrospectively evaluate changes in the average RHR and its association with cardiovascular outcomes in bisoprolol-treated coronary artery disease (CAD) patients from the CAD treated with bisoprolol (BISO-CAD) study who had comorbid hypertension. We performed ad-hoc analysis for hypertension sub-group of the BISO-CAD study (n = 866), which was a phase IV, multination, multi-center, single-arm, observational study carried out from October 2011 to July 2015 across China, South Korea, and Vietnam. Multivariate regression analysis was used to identify factors associated with incidence of composite cardiac clinical outcome (CCCO), the results were presented as adjusted odds ratio (OR) along with 95% confidence interval (CI) and adjusted P value. A total of 681 patients (mean age: 64.77 ± 10.33 years) with hypertension from BISO-CAD study were included in the analysis. Bisoprolol improved CCCOs in CAD patients with comorbid hypertension, with RHR <65 and <70 beats/min compared with RHR ≥65 and ≥75 beats/min, respectively, in the efficacy analysis (EA) set. In addition, it lowered RHR in both intent-to-treat (ITT) and EA groups after 6, 12, and 18 months of treatment. Further, RHR 70 to 74 beats/min resulted in significantly higher risk of CCCOs EA set of patients (adjusted OR: 4.34; 95% CI: 1.19-15.89; P = 0.03). Also, events of hospitalization due to acute coronary syndrome were higher when RHR 69 to 74 beats/min compared to RHR <69 beats/min in ITT patients. Bisoprolol can effectively reduce RHR in Asian CAD patients with comorbid hypertension and hence, improve CCCO without affecting their blood pressure.


Management of intracapsular femoral neck fractures in the elderly; is it time to rethink our strategy?
We reviewed 100 adult patients who had a traumatic intracapsular femoral fracture internally fixed prior to 1998, with full clinical and radiological data available. End points were complete clinical and radiological union of the fracture, non-union, avascular necrosis or fixation failure. The incidence of non-union and avascular necrosis was found to be 13 and 11%, respectively. The following factors did not influence the development of avascular necrosis or non-union; fracture displacement, screws inserted (two or three), osteoporosis, parallelism of screws, presence of screws in each "quadrant" and the experience or seniority of the surgeon. The factors influencing a poor outcome were the age of the patient at injury, reduction gap at the fracture site, alignment after reduction of the fracture especially on AP view and having all screw threads crossing beyond the fracture site. We conclude that the incidence of non-union and avascular necrosis following fixation of femoral neck fractures in our study is less than generally reported with no statistical difference between displaced and undisplaced fractures. Traditional fixation factors such as screw position and number do not seem to significantly affect the outcome with the quality of reduction being most important. Thus, the majority of patients under the age of 70 with displaced intracapsular fracture should be considered for internal fixation.


[Heart hypertrophy and heart failure--experimental findings for arrhythmogenesis].
One major cause of sudden cardiac death in heart failure is the occurrence of life-threatening polymorphic ventricular tachycardia. Especially in the early stages of heart failure half of the deaths are sudden and unexpected. The majority of these are caused by ventricular tachyarrhythmias. Whereas reentry plays a major role in patients after myocardial infarction, triggered activity is responsible for the occurrence of arrhythmic events in non-ischemic heart failure. Action potential prolongation serves as the electrophysiological basis for the formation of triggered activity and the underlying early afterdepolarizations. It has been demonstrated in heart failure and in cardiac hypertrophy that this results from a reduction in outward repolarizing ion currents, especially due to downregulation of potassium channels. The underlying substrate for the maintenance of arrhythmias in chronic heart failure in experimental models and in humans is an increase in dispersion of repolarization. It opens the floodgate to the occurrence of potentially life-threatening polymorphic ventricular arrhythmias and leads to their maintenance. Thus chronic heart failure leads to a reduced repolarization reserve, i.e. a patient-specific response to risk factors that influence repolarization. Additional risk factors in patients with heart failure are hypokalemia (diuretic therapy), bradycardia (AV block) or concomitant therapy with repolarization prolonging drugs (antiarrhythmic drugs, antibiotics etc.) that may add further stress on the repolarization process and set the stage for the occurrence of life-threatening arrhythmias. One promising therapeutic approach to suppress arrhythmias in chronic heart failure may be a selective blocking of the Na+/Ca2+ exchanger. Experimental data have recently demonstrated a reduction of action potential duration, and dispersion of repolarization as well as suppression of early afterdepolarizations and torsade de pointes in an isolated intact heart model of chronic heart failure in a proarrhythmic milieu due to block of the Na+/Ca2+ exchanger.


New diagnostic tools for delineating iron status.
Recent advances in our understanding of iron metabolism regulation and crosstalk with erythropoiesis have provided insight into the pathophysiology of multiple disease conditions. For instance, the peptide hormone hepcidin is central to the regulation of iron metabolism. Its effect on cellular iron concentration involves binding ferroportin, the main iron export protein, resulting in its internalization and degradation and leading to iron sequestration within ferroportin-expressing cells. Furthermore, hepcidin regulation by erythropoiesis is attributed in large part to a bone marrow-derived hormone erythroferrone. Erythroferrone-induced hepcidin suppression in diseases of expanded hematopoiesis results in iron overload. Conversely, diseases, such as iron refractory iron deficiency anemia and anemia of chronic inflammation, are characterized by aberrantly increased hepcidin, resulting in iron sequestration and decreased circulating iron and eventually leading to iron-restricted erythropoiesis. Lastly, because iron functions in concert with erythropoietin to promote erythroid precursor survival, proliferation, and differentiation, iron deficiency anemia is a consequence not only of decreased hemoglobin synthesis in each cell but also, a decrease in erythropoietin responsiveness in the bone marrow. How to translate this new information to the clinical setting has not been fully elucidated. The purpose of this manuscript is to summarize current standard tools for identifying iron deficiency in anemic patients; explore the tools and context for evaluating novel markers, such as hepcidin, erythroferrone, and markers of the iron restriction response; and assess available evidence for how their use could increase our understanding of health outcomes in clinically challenging cases.


Irritable bowel syndrome: a population based study.
The prevalence of irritable bowel syndrome (IBS) is relatively high, but up to now, no population based study in Iran has used the ROME III criteria. The aim of the present study was to determine the prevalence of IBS by using the ROME III criteria in the adult population of Iran. A face to face survey was conducted in a large area of the Tehran province. IBS was diagnosed by using a validated questionnaire based on the ROME III criteria. The study population comprised 18,180 participants, with a female to male ratio of 1. 15.3% of participants complained of gastrointestinal (GI) symptoms, while the prevalence of IBS was estimated to be 1.1% (139 women, 59 men, p=0.000). IBS patients were more likely to be married, and older. The most common presenting symptoms of IBS were abdominal pain that was relieved by defecation (94%), change in fecal consistency (78%), and change in bowel frequency (70%). Constipation was predominant in 52% of IBS cases, diarrhea was predominant in 18%, and 8% experienced intermittent diarrhea and constipation. The prevalence of IBS is relatively low in the Iranian adult population according to the ROME III criteria. The most probable reasons are the specificity of ROME III criteria and the characteristic low prevalence of GI symptoms in the study population.


Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke.
To design appropriate molecular genetic studies, we first need to understand the genetic epidemiology of stroke. We therefore performed a systematic review of the literature to assess the heritability of stroke according to methodological quality of studies and to determine any heterogeneity in findings between studies and possible publication bias. We searched for twin studies and studies of family history of stroke using bibliographic databases and by hand-searching reference lists and journals. Odds ratios (ORs) for family history as a risk factor for stroke were calculated within studies and combined by meta-analysis. Heterogeneity between studies, methodological quality of studies, and the influence of the age at which stroke occurred in both probands and relatives were assessed. We identified 53 independent studies (3 twin, 33 case-control, and 17 cohort). Monozygotic twins were more likely to be concordant than dizygotic twins (OR, 1.65; 95% CI, 1.2 to 2.3; P=0.003). A positive family history was a risk factor for stroke in both case-control (OR, 1.76; 95% CI, 1.7 to 1.9; P<0.00001) and cohort (OR, 1.30; 95% CI, 1.2 to 1.5; P<0.00001) studies. However, there was major heterogeneity between studies (cohort P=0.0001; case-control P<0.00001), with much stronger associations in small studies and methodologically less rigorous studies. Moreover, studies that reported insufficient data to allow meta-analysis tended to have found weaker associations. Family history of stroke was more frequent in studies that were confined to probands or relatives aged <70 years. However, few studies considered the number of affected and unaffected relatives, only 2 studies considered stroke phenotypes in detail, and only 19 studies (38%) adjusted associations for intermediate phenotypes. No twin study, only 5 cohort studies (26%), and 20 case-control studies (61%) differentiated between ischemic and hemorrhagic stroke in the proband. Family history of stroke was more frequent in large- and small-vessel stroke than in cardioembolic stroke. There were very few data on the influence of family history on stroke severity and no data on stroke recovery. Twin studies suggest a small genetic contribution to stroke, but reliable interpretation of published family history studies is undermined by major heterogeneity, insufficient detail, and potential publication and reporting bias. More detailed large-scale genetic epidemiology is required.


Heteroblastic development and shade-avoidance in response to blue and red light signals in Acacia implexa.
Information from blue (400-500 nm) and red (660-730 nm) wavelengths is used by plants to determine proximity of neighbors or actual shading. Plants undergo trait changes in order to out-compete neighbors or accommodate shading. Heteroblasty, the dramatic shift from one leaf type to another during juvenility, can be influenced by the light environment although it is unknown whether cues from blue or red (or both) are driving the developmental process. Seedlings of three populations of Acacia implexa (Mimosaceae) collected from low, medium and high rainfall habitats were grown in a factorial design of high/low blue and red light to determine how light signals affect heteroblasty and patterns of biomass allocation. Low blue light significantly delayed heteroblasty in the low rainfall population and low red light significantly delayed in the low and high rainfall populations. Low blue light increased stem elongation and decreased root biomass whereas low red light induced a strong shade-avoidance response. These results were consistent across populations although the low rainfall population showed greater trait variability in response to red light signals. We conclude that red light conveys a greater information signal than blue light that affects heteroblasty and seedling development in A. implexa.


Synthesis and biological studies of "Polycerasoidol" and "trans-δ-Tocotrienolic acid" derivatives as PPARα and/or PPARγ agonists.
2-Prenylated benzopyrans represent a class of natural and synthetic compounds showing a wide range of significant activities. Polycerasoidol is a natural prenylated benzopyran isolated from the stem bark of Polyalthia cerasoides (Annonaceae) that exhibits dual PPARα/γ agonism and an anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium. Herein, we report the synthesis of three new series of prenylated benzopyrans containing one (series 1), two (series 2, "polycerasoidol" analogs) and three (series 3, "trans-δ-tocotrienolic acid" analogs) isoprenoid units in the hydrocarbon side chain at the 2-position of the chroman-6-ol (6-hydroxy-dihydrobenzopyran) scaffold. Isoprenoid moieties were introduced through a Grignard reaction sequence, followed by Johnson-Claisen rearrangement and subsequent Wittig olefination. hPPAR transactivation activity and the structure activity relationships (SAR) of eleven novel synthesized 2-prenylated benzopyrans were explored. PPAR transactivation activity demonstrated that the seven-carbon side chain analogs (series 1) displayed selectivity for hPPARα, while the nine-carbon side chain analogs (polycerasoidol analogs, series 2) did so for hPPARγ. The side chain elongation to 11 or 13 carbons (series 3) resulted in weak dual PPARα/γ activation. Therefore, 2-prenylated benzopyrans of seven- and nine-carbon side chain (polycerasoidol analogs) are good lead compounds for developing useful candidates to prevent cardiovascular diseases associated with metabolic disorders.


Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis.
Advanced systemic mastocytosis (advSM) is characterized by presence of the KIT D816V mutation and pathologic accumulation of neoplastic mast cells (MCs) in various tissues, leading to severe symptoms and organ damage (eg, cytopenias, liver dysfunction, portal hypertension, malabsorption, and weight loss). Treatment with midostaurin, an orally active multikinase/KIT inhibitor now approved for advSM in the United States and the European Union, resulted in a high rate of response accompanied by reduced MC infiltration of the bone marrow and lowered serum tryptase level. We aimed to determine whether midostaurin improves health-related quality of life (QOL) and MC mediator-related symptoms in patients with advSM. In 116 patients with systemic mastocytosis (89 patients with advSM fulfilling the strict inclusion criteria of the D2201 study [ClinicalTrials.gov identifier NCT00782067]), QOL and symptom burden were assessed during treatment with midostaurin by using the 12-Item Short-Form Health Survey (SF-12) and the Memorial Symptom Assessment Scale patient-reported questionnaires, respectively. MC mediator-related symptoms were evaluated by using a specific physician-reported questionnaire. Over the first 6 cycles of treatment with midostaurin (ie, 6 months), patients experienced significant improvements in total SF-12 and Memorial Symptom Assessment Scale scores, as well as in subscores of each instrument. These improvements were durable during 36 months of follow-up. Similarly, we found substantial improvements (67%-100%) in all MC mediator-related symptoms. QOL and MC mediator-related symptoms significantly improve with midostaurin treatment in patients with advSM (ClinicalTrials.gov identifier, NCT00782067).


Tibial loading increases osteogenic gene expression and cortical bone volume in mature and middle-aged mice.
There are conflicting data on whether age reduces the response of the skeleton to mechanical stimuli. We examined this question in female BALB/c mice of different ages, ranging from young to middle-aged (2, 4, 7, 12 months). We first assessed markers of bone turnover in control (non-loaded) mice. Serum osteocalcin and CTX declined significantly from 2 to 4 months (p<0.001). There were similar age-related declines in tibial mRNA expression of osteoblast- and osteoclast-related genes, most notably in late osteoblast/matrix genes. For example, Col1a1 expression declined 90% from 2 to 7 months (p<0.001). We then assessed tibial responses to mechanical loading using age-specific forces to produce similar peak strains (-1300 µε endocortical; -2350 µε periosteal). Axial tibial compression was applied to the right leg for 60 cycles/day on alternate days for 1 or 6 weeks. qPCR after 1 week revealed no effect of loading in young (2-month) mice, but significant increases in osteoblast/matrix genes in older mice. For example, in 12-month old mice Col1a1 was increased 6-fold in loaded tibias vs. controls (p = 0.001). In vivo microCT after 6 weeks revealed that loaded tibias in each age group had greater cortical bone volume (BV) than contralateral control tibias (p<0.05), due to relative periosteal expansion. The loading-induced increase in cortical BV was greatest in 4-month old mice (+13%; p<0.05 vs. other ages). In summary, non-loaded female BALB/c mice exhibit an age-related decline in measures related to bone formation. Yet when subjected to tibial compression, mice from 2-12 months have an increase in cortical bone volume. Older mice respond with an upregulation of osteoblast/matrix genes, which increase to levels comparable to young mice. We conclude that mechanical loading of the tibia is anabolic for cortical bone in young and middle-aged female BALB/c mice.


Solitary eosinophilic granuloma in the frontal lobe: case report.
A rare case of a solitary eosinophilic granuloma in the brain is reported. The mass, located in the right frontal lobe, mimicked a glioma not only grossly, but also by neuroimaging. The lesion was confirmed to be an eosinophilic granuloma by electron microscopy and immunohistochemical staining for S-100 protein and HLA-DR.


Chromosomal loci associated with endosperm hardness in a malting barley cross.
A breeding objective for the malting barley industry is to produce lines with softer, plumper grain containing moderate protein content (9-12%) as they are more likely to imbibe water readily and contain more starch per grain, which in turn produces higher levels of malt extract. In a malting barley mapping population, 'Arapiles' × 'Franklin', the most significant and robust quantitative trait locus (QTL) for endosperm hardness was observed on the short arm of chromosome 1H, across three environments over two growing seasons. This accounted for 22.6% (Horsham 2000), 26.8% (Esperance 2001), and 12.0% (Tarranyurk 2001) of the genetic variance and significantly increased endosperm hardness by 2.06-3.03 SKCS hardness units. Interestingly, Arapiles and Franklin do not vary in Ha locus alleles. Therefore, this region, near the centromere on chromosome 1H, may be of great importance when aiming to manipulate endosperm hardness and malting quality. Interestingly, this region, close to the centromere on chromosome 1H, in our study, aligns with the region of the genome that includes the HvCslF9 and the HvGlb1 genes. Potentially, one or both of these genes could be considered to be candidate genes that influence endosperm hardness in the barley grain. Additional QTLs for endosperm hardness were detected on chromosomes 2H, 3H, 6H and 7H, confirming that the hardness trait in barley is complex and multigenic, similar to many malting quality traits of interest.


The integrative membrane properties of human bronchial parasympathetic Ganglia neurons.
Parasympathetic ganglia neurons in the lower airway of laboratory animals have membrane properties associated with integration of signals from the central nervous system. In this study, intracellular recordings were made from parasympathetic ganglia located on bronchi from human lungs in order to determine the level of integration provided by human neurons. Ganglion neurons were characterized as either tonic or phasic: tonic neurons responded with repetitive action potentials sustained throughout a depolarizing current step whereas phasic neurons generated one action potential and accommodated. Phasic neurons could be further differentiated as having either short or long duration after hyperpolarizing potentials following single action potentials. In phasic neurons, stimulation of preganglionic nerves elicited one or two populations of nicotinic fast excitatory postsynaptic potentials (fEPSPs) that were graded in amplitude, subthreshold for action potential generation, and decreased in amplitude during higher frequency stimulation. In tonic neurons, single preganglionic stimuli evoked two to five populations of fEPSPs, one to three of which were at threshold for action potential generation. Dye injection into the neurons revealed multiple, branching dendrites. These results provide evidence that human bronchial ganglion neurons have unique membrane properties and anatomical characteristics associated with integrating presynaptic stimuli. Changes in these properties may thus affect output from these ganglia and, consequently, autonomic tone in the lower airways.


Seed Treatment Effects on Maize Seedlings Coinfected with Fusarium spp. and Pratylenchus penetrans.
Seedling diseases of maize are caused by a complex of organisms, including fungi in the genus Fusarium. Root-lesion nematodes (Pratylenchus spp.) are common in fields where maize is grown, and they are known to interact with Fusarium spp. in several crops. The objectives of this study were to assess the impacts of seed treatment combinations on maize seedlings coinfected with Pratylenchus penetrans and two Fusarium spp. that cause seedling disease symptoms (Fusarium graminearum and F. verticillioides) and to determine whether there were interactions between P. penetrans and the Fusarium spp. Growth-chamber experiments were conducted with fungicide- or nematicide-treated or untreated maize seed planted in a sand-soil mixture infested with inoculum of either F. graminearum or F. verticillioides. A suspension of 4,000 P. penetrans (mixed stages) was added to the pots at the time of planting. After 30 days, shoot length and fresh and dry shoot and root weights were determined. Total root length and fine root length, root volume, numbers of root tips and forks, and root surface area were measured through analysis of digital images of the root systems. After 42 days, P. penetrans nematodes were extracted and quantified from roots and soil. There were significant effects of the treatments on root health with interactions between Fusarium spp. and P. penetrans. F. graminearum caused the greatest reductions in root and shoot growth, and interactions with P. penetrans were more evident for F. verticillioides than for F. graminearum. Image analysis of root system architecture showed that seed treatment significantly improved root system characteristics. Seed treatments containing the nematicide abamectin in combination with fungicides reduced root infection by P. penetrans and provided the healthiest root system when under attack by the Fusarium-Pratylenchus complex.


Early Age of the First Myopic Spectacle Prescription, as an Indicator of Early Onset of Myopia, Is a Risk Factor for High Myopia in Adulthood.
The present study investigated the risk factors for high myopia in adulthood, with a focus on the age at which children wore their first spectacles. Adults aged between 20 and 45 years were invited to complete a questionnaire about age, sex, current refractive error, high myopia in parents, early onset of myopia presented by the age of the first myopic spectacle prescription, refractive power of the first spectacles, and life habits at different educational stages. The associations between these factors and high myopia in adulthood were then evaluated and analyzed. In total, 331 participants were enrolled. Their average refractive error was -4.03 diopters, and high myopia was noted in 27.5% of the study participants. Only 3.3% of participants had fathers with high myopia, while 6.0% had mothers with high myopia. The participants received their first myopic spectacle prescription at a mean age of 13.35 years, with a mean refractive error of -1.63 diopters. The significant risk factors for developing high myopia in adult life were earlier age of the first spectacles prescribed (p < 0.001), higher refractive power of the first spectacles (p < 0.001), mother with high myopia (p=0.015), and after-school class attendance in senior high school (p=0.018). Those who wore their first spectacles at <9 years of age were more predisposed to high myopia than those who did so at ≧13 years, with an odds ratio of 24.9. The present study shows that earlier onset of myopia, which is presented by the age of the first myopic spectacle prescription, higher myopic refraction of the first spectacles, mothers with high myopia, and after-school class attendance in senior high school are risk factors for high myopia in adulthood. It suggests that delaying the onset of myopia in children is important for the prevention of high myopia in later life.


Environmental context determines multi-trophic effects of consumer species loss.
Loss of biodiversity and nutrient enrichment are two of the main human impacts on ecosystems globally, yet we understand very little about the interactive effects of multiple stressors on natural communities and how this relates to biodiversity and ecosystem functioning. Advancing our understanding requires the following: (1) incorporation of processes occurring within and among trophic levels in natural ecosystems and (2) tests of context-dependency of species loss effects. We examined the effects of loss of a key predator and two groups of its prey on algal assemblages at both ambient and enriched nutrient conditions in a marine benthic system and tested for interactions between the loss of functional diversity and nutrient enrichment on ecosystem functioning. We found that enrichment interacted with food web structure to alter the effects of species loss in natural communities. At ambient conditions, the loss of primary consumers led to an increase in biomass of algae, whereas predator loss caused a reduction in algal biomass (i.e. a trophic cascade). However, contrary to expectations, we found that nutrient enrichment negated the cascading effect of predators on algae. Moreover, algal assemblage structure varied in distinct ways in response to mussel loss, grazer loss, predator loss and with nutrient enrichment, with compensatory shifts in algal abundance driven by variation in responses of different algal species to different environmental conditions and the presence of different consumers. We identified and characterized several context-dependent mechanisms driving direct and indirect effects of consumers. Our findings highlight the need to consider environmental context when examining potential species redundancies in particular with regard to changing environmental conditions. Furthermore, non-trophic interactions based on empirical evidence must be incorporated into food web-based ecological models to improve understanding of community responses to global change.


Holocene dwarf mammoths from Wrangel Island in the Siberian Arctic.
THE cause of extinction of the woolly mammoth, Mammuthus primigenius (Blumenbach), is still debated. A major environmental change at the Pleistocene-Holocene boundary, hunting by early man, or both together are among the main explanations that have been suggested. But hardly anyone has doubted that mammoths had become extinct everywhere by around 9,500 years before present (BP). We report here new discoveries on Wrangel Island in the Arctic Ocean that force this view to be revised. Along with normal-sized mammoth fossils dating to the end of the Pleistocene, numerous teeth of dwarf mammoth dated 7,000-4,000 yr BP have been found there. The island is thought to have become separated from the mainland by 12,000 yr BP. Survival of a mammoth population may be explained by local topography and climatic features, which permitted relictual preservation of communities of steppe plants. We interpret the dwarfing of the Wrangel mammoths as a result of the insularity effect, combined with a response to the general trend towards unfavourable environment in the Holocene.


Thyroid-Stimulating Hormone Levels Are Positively Associated with Insulin Resistance.
BACKGROUND It has been reported that overt and mild thyroid dysfunctions are associated with insulin resistance (IR). We performed this retrospective study to evaluate the relationships between thyroid-stimulating hormone (TSH) levels within the reference range and IR. MATERIAL AND METHODS A total of 447 outpatients were enrolled in this study: 298 with type 2 diabetes mellitus and 149 nondiabetic individuals. Based on a cutoff HbA1c value of 7%, diabetic patients were additionally divided into 2 groups: a high-HbA1c group (n=240) and a low-HbA1c group (n=58). The relationships of TSH levels and HOMA-IR were computed using linear regression models. RESULTS TSH levels were positively and linearly associated with HOMA-IR in both the nondiabetic and diabetic groups (r=0.210, p=0.011 and r=0.451, p<0.001), as well as in the high- and low-HbA1c groups (r=0.507, p<0.001 and r=0.259, p=0.048). A better correlation between TSH levels and HOMA-IR was found in the diabetic group and in the high-HbA1c group when compared with the nondiabetic group and the low-HbA1c group, respectively. Linear regression analysis showed that TSH levels were independently associated with HOMA-IR (p=0.034, =0.049 and <0.001 in nondiabetic, low-, and high-HbA1c groups, respectively). CONCLUSIONS Our data suggest that TSH is independently associated with insulin resistance.


Out in the cold and sick: low temperatures and fungal infections impair a frog's skin defenses.
Amphibians worldwide continue to battle an emerging infectious disease, chytridiomycosis, caused by Batrachochytrium dendrobatidis (Bd). Southern leopard frogs, Rana sphenocephala, are known to become infected with this pathogen, yet they are considered 'of least concern' for declines due to chytridiomycosis. Previous studies have shown that R. sphenocephala secretes four antimicrobial peptides (AMPs) onto their skin which may play an important role in limiting susceptibility to chytridiomycosis. Here, we examined (1) the effects of temperature and AMP depletion on infections with Bd and (2) the effects of temperature and Bd infection on the capacity to secrete AMPs in juvenile leopard frogs. Pathogen burden and mortality were greater in frogs exposed to Bd at low temperature but did not increase following monthly AMP depletion. Both low temperature and Bd exposure reduced the capacity of juvenile frogs to restore peptides after monthly depletions. Frogs held at 14°C were poorly able to restore peptides in comparison with those at 26°C. Frogs held at 26°C were better able to restore their peptides, but when exposed to Bd, this capacity was significantly reduced. These results strongly support the hypothesis that both colder temperatures and Bd infection impair the capacity of juvenile frogs to produce and secrete AMPs, an important component of their innate defense against chytrid fungi and other pathogens. Thus, in the face of unpredictable climate changes and enzootic pathogens, assessments of disease risk should consider the potential for effects of environmental variation and pathogen exposure on the quality of host defenses.


Tissue-restricted expression of the cardiac alpha-myosin heavy chain gene is controlled by a downstream repressor element containing a palindrome of two ets-binding sites.
The expression of the alpha-myosin heavy chain (MHC) gene is restricted primarily to cardiac myocytes. To date, several positive regulatory elements and their binding factors involved in alpha-MHC gene regulation have been identified; however, the mechanism restricting the expression of this gene to cardiac myocytes has yet to be elucidated. In this study, we have identified by using sequential deletion mutants of the rat cardiac alpha-MHC gene a 30-bp purine-rich negative regulatory (PNR) element located in the first intronic region that appeared to be essential for the tissue-specific expression of the alpha-MHC gene. Removal of this element alone elevated (20- to 30-fold) the expression of the alpha-MHC gene in cardiac myocyte cultures and in heart muscle directly injected with plasmid DNA. Surprisingly, this deletion also allowed a significant expression of the alpha-MHC gene in HeLa and other nonmuscle cells, where it is normally inactive. The PNR element required upstream sequences of the alpha-MHC gene for negative gene regulation. By DNase I footprint analysis of the PNR element, a palindrome of two high-affinity Ets-binding sites (CTTCCCTGGAAG) was identified. Furthermore, by analyses of site-specific base-pair mutation, mobility gel shift competition, and UV cross-linking, two different Ets-like proteins from cardiac and HeLa cell nuclear extracts were found to bind to the PNR motif. Moreover, the activity of the PNR-binding factor was found to be increased two- to threefold in adult rat hearts subjected to pressure overload hypertrophy, where the alpha-MHC gene is usually suppressed. These data demonstrate that the PNR element plays a dual role, both downregulating the expression of the alpha-MHC gene in cardiac myocytes and silencing the muscle gene activity in nonmuscle cells. Similar palindromic Ets-binding motifs are found conserved in the alpha-MHC genes from different species and in other cardiac myocyte-restricted genes. These results are the first to reveal a role of the Ets class of proteins in controlling the tissue-specific expression of a cardiac muscle gene.


Association of chronic kidney disease and anemia with physical capacity: the heart and soul study.
Chronic kidney disease (CKD) and anemia are common conditions in the outpatient setting, but their independent and additive effects on physical capacity have not been well characterized. The association of CKD and anemia with self-reported physical function was evaluated and exercise capacity was measured in patients with coronary disease. A cross-sectional study of 954 outpatients enrolled in the Heart and Soul study was performed. CKD was defined as a measured creatinine clearance <60 ml/min, and anemia was defined as a hemoglobin level of <12g/dl. Physical function was self-assessed using the physical limitation subscale of the Seattle Angina Questionnaire (0 to 100), and exercise capacity was defined as metabolic equivalent tasks achieved at peak exercise. In unadjusted analyses, CKD was associated with lower self-reported physical function (67.6 versus 74.9; P < 0.001) and lower exercise capacity (5.5 versus 7.9; P < 0.001). Similarly, anemia was associated with lower self-reported physical function (62.6 versus 74.3; P < 0.001) and exercise capacity (5.7 versus 7.5; P < 0.001). After multivariate adjustment, CKD (69.4 versus 74.2; P = 0.003) and anemia (67.5 versus 73.6; P = 0.009) each remained associated with lower mean self-reported physical function. In addition, patients with CKD (6.3 versus 7.7; P < 0.001) or anemia (6.5 versus 7.4; P = 0.004) had lower adjusted mean exercise capacities. Participants with both CKD and anemia had lower self-reported physical function and exercise capacity than those with either alone. CKD and anemia are independently associated with physical limitation and reduced exercise capacity in outpatients with coronary disease, and these effects are additive. The broad impact of these disease conditions merits further study.


An integrated platform for image-guided cardiac resynchronization therapy.
Cardiac resynchronization therapy (CRT) is an effective procedure for patients with heart failure but 30% of patients do not respond. This may be due to sub-optimal placement of the left ventricular (LV) lead. It is hypothesized that the use of cardiac anatomy, myocardial scar distribution and dyssynchrony information, derived from cardiac magnetic resonance imaging (MRI), may improve outcome by guiding the physician for optimal LV lead positioning. Whole heart MR data can be processed to yield detailed anatomical models including the coronary veins. Cine MR data can be used to measure the motion of the LV to determine which regions are late-activating. Finally, delayed Gadolinium enhancement imaging can be used to detect regions of scarring. This paper presents a complete platform for the guidance of CRT using pre-procedural MR data combined with live x-ray fluoroscopy. The platform was used for 21 patients undergoing CRT in a standard catheterization laboratory. The patients underwent cardiac MRI prior to their procedure. For each patient, a MRI-derived cardiac model, showing the LV lead targets, was registered to x-ray fluoroscopy using multiple views of a catheter looped in the right atrium. Registration was maintained throughout the procedure by a combination of C-arm/x-ray table tracking and respiratory motion compensation. Validation of the registration between the three-dimensional (3D) roadmap and the 2D x-ray images was performed using balloon occlusion coronary venograms. A 2D registration error of 1.2 ± 0.7 mm was achieved. In addition, a novel navigation technique was developed, called Cardiac Unfold, where an entire cardiac chamber is unfolded from 3D to 2D along with all relevant anatomical and functional information and coupled to real-time device detection. This allowed more intuitive navigation as the entire 3D scene was displayed simultaneously on a 2D plot. The accuracy of the unfold navigation was assessed off-line using 13 patient data sets by computing the registration error of the LV pacing lead electrodes which was found to be 2.2 ± 0.9 mm. Furthermore, the use of Unfold Navigation was demonstrated in real-time for four clinical cases.


[The effects of crime information and response effectiveness on behavioral intentions of coping with crime].
A survey and an experiment were conducted about the promotion of behavioral intentions for preventing sexual assaults by strangers. The study focused on the "identifiable victim effect", where contextual descriptions of a single victim resulted in the collection of more donations than statistical descriptions of victims. A survey of 42 police websites that made recommendation for preventing sexual assaults revealed that only 3.3% of the threat messages described identifiable victims, whereas 50.0% referred to statistical figures. Additionally, only 9.5% of the coping recommendations mentioned the effectiveness of the recommendation. In the experiment, 207 female university students were randomly presented with one of four threat messages featuring victims (statistical, identifiable, combination, or none), followed by recommendation of high-efficacy or low-efficacy response. ANOVA indicated interaction effects of threat type and response efficacy on behavioral intentions. The effect of threat messages was statistically significant only when a high-efficacy response was recommended. The difference in behavioral intentions for different types of threats partly replicated the findings in donation. These results suggest that current threat appeals for crime prevention need refinements regarding both the threat description and response the efficacy.


Control of seed dormancy in Nicotiana plumbaginifolia: post-imbibition abscisic acid synthesis imposes dormancy maintenance.
The physiological characteristics of seed dormancy in Nicotiana plumbaginifolia Viv. are described. The level of seed dormancy is defined by the delay in seed germination (i.e the time required prior to germination) under favourable environmental conditions. A wild-type line shows a clear primary dormancy, which is suppressed by afterripening, whereas an abscisic acid (ABA)-deficient mutant shows a non-dormant phenotype. We have investigated the role of ABA and gibberellic acid (GA(3)) in the control of dormancy maintenance or breakage during imbibition in suitable conditions. It was found that fluridone, a carotenoid biosynthesis inhibitor, is almost as efficient as GA(3) in breaking dormancy. Dry dormant seeds contained more ABA than dry afterripened seeds and, during early imbibition, there was an accumulation of ABA in dormant seeds, but not in afterripened seeds. In addition, fluridone and exogenous GA(3) inhibited the accumulation of ABA in imbibed dormant seeds. This reveals an important role for ABA synthesis in dormancy maintenance in imbibed seeds.


Large-Scale Brain Networks Supporting Divided Attention across Spatial Locations and Sensory Modalities.
Higher-order cognitive processes were shown to rely on the interplay between large-scale neural networks. However, brain networks involved with the capability to split attentional resource over multiple spatial locations and multiple stimuli or sensory modalities have been largely unexplored to date. Here I re-analyzed data from Santangelo et al. (2010) to explore the causal interactions between large-scale brain networks during divided attention. During fMRI scanning, participants monitored streams of visual and/or auditory stimuli in one or two spatial locations for detection of occasional targets. This design allowed comparing a condition in which participants monitored one stimulus/modality (either visual or auditory) in two spatial locations vs. a condition in which participants monitored two stimuli/modalities (both visual and auditory) in one spatial location. The analysis of the independent components (ICs) revealed that dividing attentional resources across two spatial locations necessitated a brain network involving the left ventro- and dorso-lateral prefrontal cortex plus the posterior parietal cortex, including the intraparietal sulcus (IPS) and the angular gyrus, bilaterally. The analysis of Granger causality highlighted that the activity of lateral prefrontal regions were predictive of the activity of all of the posteriors parietal nodes. By contrast, dividing attention across two sensory modalities necessitated a brain network including nodes belonging to the dorsal frontoparietal network, i.e., the bilateral frontal eye-fields (FEF) and IPS, plus nodes belonging to the salience network, i.e., the anterior cingulated cortex and the left and right anterior insular cortex (aIC). The analysis of Granger causality highlights a tight interdependence between the dorsal frontoparietal and salience nodes in trials requiring divided attention between different sensory modalities. The current findings therefore highlighted a dissociation among brain networks implicated during divided attention across spatial locations and sensory modalities, pointing out the importance of investigating effective connectivity of large-scale brain networks supporting complex behavior.


A new experimental and clinical approach of combining usage of highly active tumor-infiltrating lymphocytes and highly sensitive antitumor drugs for the advanced malignant tumor.
In recent years, tumor-infiltrating lymphocytes (TILs) have been reported to be effective for tumors in experimental and clinical research. In order to increase the therapeutical effect, we modified some steps of Rosenberg's approach: a. cold digestion with collagenase at 4 degrees C for 24 hours; b. sedimentation instead of centrifugation; c. elimination of tumor cells before the cultivation procedure. Compared with the original approach, the proliferation, activity and cytotoxicity of TILs obtained by the modified procedure were much improved. TILs' expansion-fold was greater than that with the original approach. Cytotoxicity against tumor cells was more potent. Increased TILs' subsets were CD3 and CD8 cells. Meanwhile, we took tumor cells from tumor tissues to test their in vitro chemosensitivities to different drugs in order to select highly sensitive antitumor drugs for treatment of cases with advanced tumors. According to the design of using highly active TILs and highly sensitive drugs (H & H therapy), preliminary clinical results of 50 cases showed higher response rates than those in treatment with TIL/IL2, LAK/IL2 and TIL+IL2+CTX. Less toxic side effects were observed in 14 patients.


Mutations in PGRN gene associated with the risk of psoriasis in Pakistan: a case control study.
Psoriasis is a chronic, autoimmune, papulosquamous skin disorder, characterized by the formation of drop-like papules and silvery-white plaques surrounded by reddened or inflamed skin, existing predominantly on the scalp, knees and elbows. The characteristic inflammation and hyperproliferation of keratinocytes in psoriasis is regulated by progranulin (PGRN), which suppresses the expression and release of inflammatory cytokines, such as TNF-α. In this study mutation analysis of the PGRN gene was performed by extracting the genomic DNA from blood samples of 171 diagnosed psoriasis patients and controls through standard salting-out method, followed by amplification and sequencing of the targeted region of exon 5-7 of PGRN gene. Three single nucleotide polymorphisms, rs25646, rs850713 and a novel point mutation 805A/G were identified in the PGRN gene with significant association with the disease. The variant alleles of the polymorphisms were significantly distributed among cases and controls, and statistical analysis suggested that the mutant genotypes conferred a higher risk of psoriasis development and progression. Multi-SNP haplotype analysis indicated that the CAA (OR = 8.085, 95% CI = 5.16-12.66) and the CAG (OR = 3.204, 95% CI = 1.97-5.21) haplotypes were significantly associated with psoriasis pathogenesis. These findings demonstrate that polymorphisms in PGRN might act as potential molecular targets for early diagnosis of psoriasis in susceptible individuals.


Activation of complement and neutrophils increases vascular permeability during air embolism.
Pulmonary air embolism occurs in diving and aviation during acute pressure reductions and in clinical complications. Undoubtedly physical obstructions play a role, but bubbles in blood can produce a number of indirect effects leading to tissue injury. In the present study, we investigated the involvement of the complement system and polymorphonuclear leukocytes (PMN) in altering segmental vascular resistance, lung weight gain, and filtration coefficient (Kf), by using isolated and perfused rat lungs. After establishing ventilation with air and 5% CO2, the lung was removed en bloc and suspended in a humidified chamber at 37 degrees C. Lung weight and arterial and venous pressures were monitored continuously. The buffered salt perfusate contains 4% Ficoll for osmotic balance. We used four series of perfusates containing 20% of: a) normal plasma; b) decomplemented plasma (from donor rats pretreated with a cobra venom factor); c) normal plasma and PMN at 2 x 10(6).ml-1; and d) decomplemented plasma and PMN at 2 x 10(6).ml-1. Pulmonary air embolism, air bubbles introduced through the pulmonary artery, increased pulmonary arterial resistance and pulmonary arterial blood pressure. The lung weight and lung water content were greater than those in the control groups. Air embolism increased vascular permeability, which was shown by an elevated Kf after air infusion. After air embolism, Kf was 0.63 +/- 0.05 g.min-1.cm H2O-1.100 g-1 in lungs perfused with both PMN and plasma, which was significantly greater than those in lungs perfused with either plasma (0.49 +/- 0.04), decomplemented plasma (0.44 +/- 0.03), or PMN and decomplemented plasma (0.47 +/- 0.03). These results demonstrated that air embolism increases vascular permeability of the lung by pulmonary hypertension, activation of the complement, and activation of PMN.


Patient-focused care and the future of radiography.
Reforming the U.S. health care system to make medical services affordable and accessible to all Americans will require dramatic change. In fact, many of the reform strategies that have been proposed would revolutionize the way medical care is delivered in this country. One such proposal is the patient-focused care model. As its name implies, PFCM would redesign hospital operations to place patients at the center of all activity. Thus, PFCM has ramifications not only on bottom-line medical costs, but also on organizational structure, the efficiency and quality of service, employee relations, educational standards, professionalism and job satisfaction. This article describes PFCM and its potential positive and negative effects on health care delivery in the United States, with particular emphasis on its impact on radiologic technologists.


Experience in third molar surgery: an update.
The relationship between a surgeon's experience and the incidence of postoperative complications after third molar surgery is assessed in this prospective clinical study. Previous reports have shown this to be one the most influential factors on surgical outcome. In this study, 3,236 patients underwent surgical removal of impacted third molars. All patients included in the study were reviewed and the various postoperative complications were recorded and statistically compared to the surgeon's grade. Patients' demographics and pre-operative radiographic findings were also noted. The surgical procedures were performed by seven specialists and 12 residents. In the group of patients treated by the residents, the incidence of postoperative complications was found to be significant with regards to trismus, infection, alveolar osteitis and paraesthesia of the lingual and inferior alveolar nerves. In the group of patients treated by specialists, the incidence of postoperative bleeding was found to be statistically significant. There is without doubt a relationship between the surgeon's experience and the postoperative complication in third molar surgery. The impact of the findings from this study upon the profession, education and research is as yet unrealised. The ethical and moral implications of our findings are discussed.


A case of apparent trisomy 21 without the Down's syndrome phenotype.
We describe a case of apparent trisomy 21 that does not fulfill the criteria for the clinical diagnosis of Down's syndrome (DS). Our patient was subjected to karyotype analysis and found to have full, non-mosaic trisomy 21 in both blood lymphocytes and skin fibroblasts, while examination of the term placenta, which was performed earlier in the course of a different study, had shown mosaicism (73%) for trisomy 21. FISH analysis showed no obvious rearrangement of the DS chromosomal region in any of the chromosomes 21. Molecular analysis using polymorphic markers on chromosome 21 verified the existence of trisomy for the entire long arm of the chromosome and showed that the origin of the extra chromosome was maternal and was probably the result of a mitotic error. In contrast with the above, the clinical evaluation using the Jackson checklist of 25 signs failed to establish the diagnosis of DS. We believe that our patient might present mosaicism in other tissues that are not available for analysis and can be regarded as an extreme example in the continuous spectrum of karyotype phenotype associations in mosaic cases.


Evaluation of Allergic Diseases, Symptom Control, and Relation to Infections in a Group of Italian Elite Mountain Bikers.
This study estimates the prevalence of allergic diseases in a group of Italian elite mountain bikers, compares the prevalence of infectious episodes between allergic and nonallergic athletes, and evaluates asthma and rhinitis symptom control in allergic athletes. Two hundred twenty-six Italian nonsmoking mountain bikers received by mail the Allergy Questionnaire for Athletes (AQUA) and completed it. The RhinAsthma Patient Perspective (RAPP) questionnaire was sent to the 108 participants with a positive AQUA score and 104 returned the questionnaire. Athletes with an AQUA score ≥5 or <5 were defined AQUA+ (allergic) or AQUA- (nonallergic), respectively. RhinAsthma Patient Perspective questionnaire total score ≥15 was indicative of a poor control of symptoms. Of the 226 athletes, 47.8% were AQUA+, whereas 52.2% were AQUA-. A higher number of AQUA+ athletes reported frequent upper respiratory tract infections (URTIs) and herpes labialis than AQUA- athletes (P < 0.001), and the prevalence of URTI was greater in the subgroup of AQUA+ athletes who trained ≥3 hours per session. According to RAPP questionnaire score, 21.1% of AQUA+ mountain bikers had a poor control of asthma and rhinitis symptoms. Our study shows a high prevalence of allergy among Italian elite mountain bikers whose asthma and rhinitis symptoms are poorly controlled in about a fifth of the sample. Allergic athletes, mainly those training more than 3 hours per session, are at higher risk of URTI and herpes labialis. Screening programs to detect allergic diseases and to evaluate symptom control in athletes should be strongly encouraged.


Thermal Expansion of Metal-Organic Framework Crystal-Glass Composites.
Metal-organic framework crystal-glass composites (MOF CGCs) are a class of materials comprising a crystalline framework embedded within a MOF glass matrix. Herein, we investigate the thermal expansion behavior of three MOF CGCs, incorporating two flexible (MIL-53(Al) and MIL-118) and one rigid (UL-MOF-1) MOF within a ZIF-62 glass matrix. Specifically, variable-temperature powder X-ray diffraction data and thermomechanical analysis show the suppression of thermal expansivity in each of these three crystalline MOFs when suspended within a ZIF-62 glass matrix. In particular, for the two flexible frameworks, the average volumetric thermal expansion (β) was found to be near-zero in the crystal-glass composite. These results provide a route to engineering thermal expansivity in stimuli-responsive MOF glass composites.


Is transactional sex exploitative? A social norms perspective, with implications for interventions with adolescent girls and young women in Tanzania.
Although transactional sex is common in many sexual relationships, there has been little research into the degree to which the practice is considered exploitative in the settings in which it is practiced. We describe the social norms that influence transactional sex in two sites in Mwanza, Tanzania, and explore local understandings of whether and under what conditions it is considered exploitative. We then compare these "emic" understandings of exploitation to international definitions and norms around sexual exploitation. This study employed a qualitative research design involving 18 focus group discussions and 43 in-depth interviews with young people aged 14-24 years and parents with children aged 14-24 years in a rural area and an urban center within Mwanza, Tanzania. Thematic analysis was conducted with the aid of NVivo 10. The social norms influencing the practice of transactional sex included: reciprocity as a core cultural value that permeates the way exchange in sexual relationships is judged; gendered expectations that men should provide for women's material needs in sexual relationships and that women should reciprocate by means of sex; and peer pressure to be perceived as "fashionable". Adolescent girls and young women (AGYW) are under strong peer pressure to conform to a "modern lifestyle" as reflected in stylish clothing and other items of modernity such as cellphones. The emic conceptualization of exploitation is defined by circumstances surrounding the relationship or a sexual encounter. Important factors that characterize local notions of when transactional relationships are considered exploitative include: when the encounter or relationship involves an imbalance of power (based on age, male economic power and social status); when a man fails to reciprocate; and when sex is coerced. According to community perspectives, young women's behavior should be considered exploitative of men when they take gifts or money yet refuse sex or when they demand large sums of money. Interventions aimed at reducing AGYW's exploitation through transactional sex need to be cognizant of the variations in the understanding of what constitutes sexual exploitation as well as the social and gender norms influencing the practice of transactional sex. Interventions need to involve communities and families in critical thinking that helps them identify positive alternatives to current gendered social norms that shape the involvement of AGYW and men in transactional sex.


[Improvement of graft fixation methods for reconstruction of the anterior cruciate ligament].
In N. N. Priorov Institute of Traumatology and Orthopedics, atografts with bone blocks have been extensively used over the last 10 years to reconstruct anterior cruciate ligament after sports, ballet, and circus injuries. The autografts are fixed by interference screws at the level of the articular space. Reconstruction of the anterior cruciate ligament by this technique was performed in more than 800 patients (99%) between 1998 and 2006. Positive outcome was achieved in the majority of the cases (93%). A more universal method for the fixation of autografts with bone blocks has been employed since 2005 using polylactic acid pins, the Rigidfix system, and Milago interference screws. The Rigidfix system is most suitable for revisional reconstruction and may serve as an alternative tool for the primary reconstruction of the anterior cruciate ligament.


[Photoperiodic control of gonadal endocrine function in silver-gray foxes and its alteration during domestication].
Studies have been made on the level of estradiol and progesterone in domesticated and nondomesticated female silver foxes under different photoperiodic regime. The duration of the "light--darkness" cycle was equal to 24 h. Total duration of the light period was equal to 9 1/2 h; illumination was natural for 7 h, being artificial for the rest 2 1/2 h in a dark part of a day. It was demonstrated that additional illumination affects the hormonal level and sexual activity, the effect being dependent on the particular time of illumination. Nocturnal illumination significantly increased the level of sex hormones in the blood, domesticated animals being more sensitive as compared to nondomesticated ones.


The impact of a stroke screening program.
Stroke is a leading cause of serious disability and is the third leading cause of death in the United States. Prevention and early intervention are key to reducing death and disability from stroke. This study investigated the impact of a community-based stroke-screening program on the knowledge of participants regarding signs and symptoms of stroke, related emergency action, and personal risk factors for stroke. Self-reported behavioral changes were also recorded. Initial data were collected at the screening site as part of the program, and follow-up data were collected by telephone interview at 1, 3, and 6-month intervals after the screening. Of the 107 people who participated in the screening, 85 (79%) participated in all three follow-up interviews. Findings indicate that participants in this community-based stroke-screening program showed increases in their knowledge about stroke, including what a stroke is, signs and symptoms, related emergency action, personal risk factors, and ways to reduce risk. Furthermore, the findings demonstrate that the knowledge was retained throughout the study period. Approximately half of the participants also reported having made at least one behavioral change to reduce their stroke risk.


Examining the relationship of vaping to smoking initiation among US youth and young adults: a reality check.
The 2018 National Academies of Sciences, Engineering, and Medicine Report found substantial evidence that electronic cigarette use (vaping) by youth is strongly associated with an increased risk of ever using cigarettes (smoking) and moderately associated with progressing to more established smoking. However, the Report also noted that recent increases in vaping have been associated with declining rates of youth smoking. This paper examines the temporal relationship between vaping and youth smoking using multiple data sets to explore the question of whether vaping promotes smoking initiation in the USA. Using publicly available, nationally representative data on smoking and vaping among youth and young adults, we conducted a trend line analysis of deviations from long-term trends in smoking starting from when vaping became more prevalent. There was a substantial increase in youth vaping prevalence beginning in about 2014. Time trend analyses showed that the decline in past 30-day smoking prevalence accelerated by two to four times after 2014. Indicators of more established smoking rates, including the proportion of daily smokers among past 30-day smokers, also decreased more rapidly as vaping became more prevalent. The inverse relationship between vaping and smoking was robust across different data sets for both youth and young adults and for current and more established smoking. While trying electronic cigarettes may causally increase smoking among some youth, the aggregate effect at the population level appears to be negligible given the reduction in smoking initiation during the period of vaping's ascendance.


Faculty development in medical education research: a cooperative model.
As the definition of scholarship is clarified, each specialty should develop a cadre of medical education researchers who can design, test, and optimize educational interventions. In 2004, the Association for American Medical Colleges' Group on Educational Affairs developed the Medical Education Research Certificate (MERC) program to provide a curriculum to help medical educators acquire or enhance skills in medical education research, to promote effective collaboration with seasoned researchers, and to create better consumers of medical education scholarship. MERC courses are offered to individuals during educational meetings. Educational leaders in emergency medicine (EM) identified a disparity between the "scholarship of teaching" and medical education research skills, and they collaborated with the MERC steering committee to develop a mentored faculty development program in medical education research. A planning committee comprising experienced medical education researchers who are also board-certified, full-time EM faculty members designed a novel approach to the MERC curriculum: a mentored team approach to learning, grounded in collaborative medical education research projects. The planning committee identified areas of research interest among participants and formed working groups to collaborate on research projects during standard MERC workshops. Rather than focusing on individual questions during the course, each mentored group identified a single study hypothesis. After completing the first three workshops, group members worked under their mentors' guidance on their multiinstitutional research projects. The expected benefits of this approach to MERC include establishing a research community network, creating projects whose enrollments offer a multiinstitutional dimension, and developing a cadre of trained education researchers in EM.


DNA extraction and PCR assays for detection of Toxoplasma gondii.
For detection of Toxoplasma gondii we compared the sensitivity of two different DNA extraction methods and three different PCR assays. Sensitivities of DNA extraction by QIAamp DNA mini Kit or MagNa pure followed by PCR, nested PCR and oligochromatography or Light Cycler PCR using either SYBR green chemistry or TaqMan probe were compared. No significant difference between extraction methods was found using pure T. gondii tachyzoites. Spiked blood samples, 10(4) to 10 parasites per sample, generated no difference in sensitivity between the two DNA extraction methods when analysed by nested PCR detected by oligochromatography or analysed by Light Cycler PCR TaqMan. In spiked blood samples Light Cycler PCR SYBR green was unable to detect the parasite and a reduction in sensitivity was observed with the TaqMan assay. Conventional PCR was more sensitive when DNA was extracted from the spiked samples using the QIAamp DNA mini Kit. Conventional and nested PCR were found to be more sensitive than Light Cycler PCR TaqMan using the QIAamp DNA mini Kit. It was not possible to use Light Cycler PCR SYBR green in blood samples. Conventional PCR was more sensitive for detection of T. gondii in spiked blood samples using QIAamp DNA mini Kit DNA extraction, suggesting that the choice of DNA extraction method may affect PCR assays differently.


Comprehensive investigation of the presence of JC virus in AIDS patients with and without progressive multifocal leukoencephalopathy.
Progressive multifocal leukoencephalopathy (PML), a viral-induced demyelinating disease, is becoming relatively common, while many diagnostic and pathogenetic aspects remain to be clarified. A study was therefore undertaken in 64 AIDS patients suffering from various neurological disorders, including PML (12 subjects), with the specific objective of searching for JC virus (JCV) DNA by nested PCR (n-PCR) in cerebrospinal fluid (CSF), peripheral blood mononuclear cells (PBMCs), and urine collected from all patients. CSF examination, CD4 and CD8 counts, neurological examinations, and neuroradiological investigations were undertaken. JCV DNA was detected in 92% of CSF specimens in 75% of the PBMCs and urine samples from the PML patients, whereas among the non-PML patients JCV DNA was not detected in any CSF samples, but was found in 10% of PBMCs and in 39% of the urine specimens. BKV and JCV DNA viruria was observed simultaneously in 6% of the AIDS patients without PML. The routine CSF tests including IgG oligoclonal bands, the Link, and Tourtellotte IgG indexes, did not show a typical pattern in PML cases. The data obtained clearly indicate that the detection of JCV DNA in CSF constitutes an efficient marker for PML diagnosis. The simultaneous presence of JCV DNA in the CSF, PBMCs, and urine samples from the PML patients, who did not differ from controls with regard to their immunosuppressive status, suggests that JCV could be carried into the central nervous system (CNS) by infected PBMCs.


The impact of hospital nursing characteristics on 30-day mortality.
Evidence indicates that hospital nursing characteristics such as staffing contribute to patient outcomes. Less attention has been given to other hospital nursing characteristics central to optimal professional practice, namely nurse education and skill mix, continuity of care, and quality of the work environment. To assess the relative effects and importance of nurse education and skill mix, continuity of care, and quality of work environment in predicting 30-day mortality after adjusting for institutional factors and individual patients characteristics. A cross-sectional analysis of outcome data for 18,142 patients discharged from 49 acute care hospitals in Alberta, Canada, for diagnoses of acute myocardial infarction, congestive heart failure, chronic obstructive pulmonary disease, pneumonia, or stroke between April 1, 1998, and March 31, 1999, was done. Mortality data were linked to patient demographic and comorbidity factors, institutional characteristics, and hospital nursing characteristics derived from a survey of all registered nurses working in acute care hospitals. Using multilevel analysis, it was determined that the log-odds for 30-day mortality varied significantly across hospitals (variance .044, p < .001). Patient comorbidities and age explained 44.2% of the variance in 30-day mortality. After adjustment for patient comorbidities and demographic factors, and the size, teaching, and urban status of the study hospitals in a fixed-effects model, the odds ratios (95% confidence interval) of the significant hospital nursing characteristics that predict 30-day mortality were as follows: 0.81 (0.68-0.96) for higher nurse education level, 0.83 (0.73-0.96) for richer nurse skill mix, 1.26 (1.09-1.47) for higher proportion of casual or temporary positions, and 0.74 (0.6-00.91) for greater nurse-physician relationships. The institutional and hospital nursing characteristics explained an additional 36.9%. Hospital nursing characteristics are an important consideration in efforts to reduce the risk of 30-day mortality of patients.


Development of gamma G, gamma A, gamma M, beta IC-beta IA, C 1 esterase inhibitor, ceruloplasmin, transferrin, hemopexin, haptoglobin, fibrinogen, plasminogen, alpha 1-antitrypsin, orosomucoid, beta-lipoprotein, alpha 2-macroglobulin, and prealbumin in the human conceptus.
The synthesis of gammaG, gammaA, gammaM, beta(1C)/beta(1A), C'1 esterase inhibitor, ceruloplasmin, transferrin, hemopexin, haptoglobin, fibrinogen, alpha(1)-antitrypsin, orosomucoid, beta-lipoprotein, alpha(2)-macroglobulin, and prealbumin was studied in 15 normal human embryos and fetuses of 29 days to 18 wk gestation and in the yolk sacs of four embryos from 5.5 to 11.5 wk gestation using tissue culture in (14)C-labeled amino acids followed by radioimmunoelectrophoresis. The human embryo as early as 29 day gestation synthesized beta(1C)/beta(1A), C'1 esterase inhibitor, transferrin, hemopexin, alpha(1)-antitrypsin, beta-lipoprotein, alpha(2)-macroglobulin, and prealbumin in culture. At 32 days gestation ceruloplasmin and orosomucoid were also synthesized, but synthesis of fibrinogen was not observed before 5.5 wk. Synthesis of gammaM occurred as early as 10.5 wk gestation, and gammaG synthesis was found in cultures as early as 12 wk gestation; gammaA synthesis was not detected in any of the tissue cultures. With the exception of the gamma-globulins, each of the proteins studied was synthesized by the liver, but additional sites of synthesis for some of these proteins were also found. Synthesis of gammaG and gammaM occurred primarily in the spleen, but other sites of synthesis were noted as well. Changes in the concentrations of most of these proteins and plasminogen in embryonic and fetal serum from 5.5 to 41 wk gestation, in amniotic fluid from 6.5 to 38 wk gestation, and in the sera of neonates during the 1st 3 wk postpartum are described. Although gammaA, gammaM, ceruloplasmin, or haptoglobin were not detectable in some of the embryonic and fetal sera, gammaA and ceruloplasmin were both present as early as 6.5 wk gestation, haptoglobin by 9.5 wk gestation, and gammaM by 17 wk gestation. Each of the other proteins were present in all of the sera examined.


Role and regulation of the Flp/Tad pilus in the virulence of Pectobacterium atrosepticum SCRI1043 and Pectobacterium wasabiae SCC3193.
In this study, we characterized a putative Flp/Tad pilus-encoding gene cluster, and we examined its regulation at the transcriptional level and its role in the virulence of potato pathogenic enterobacteria of the genus Pectobacterium. The Flp/Tad pilus-encoding gene clusters in Pectobacterium atrosepticum, Pectobacterium wasabiae and Pectobacterium aroidearum were compared to previously characterized flp/tad gene clusters, including that of the well-studied Flp/Tad pilus model organism Aggregatibacter actinomycetemcomitans, in which this pilus is a major virulence determinant. Comparative analyses revealed substantial protein sequence similarity and open reading frame synteny between the previously characterized flp/tad gene clusters and the cluster in Pectobacterium, suggesting that the predicted flp/tad gene cluster in Pectobacterium encodes a Flp/Tad pilus-like structure. We detected genes for a novel two-component system adjacent to the flp/tad gene cluster in Pectobacterium, and mutant analysis demonstrated that this system has a positive effect on the transcription of selected Flp/Tad pilus biogenesis genes, suggesting that this response regulator regulate the flp/tad gene cluster. Mutagenesis of either the predicted regulator gene or selected Flp/Tad pilus biogenesis genes had a significant impact on the maceration ability of the bacterial strains in potato tubers, indicating that the Flp/Tad pilus-encoding gene cluster represents a novel virulence determinant in Pectobacterium. Soft-rot enterobacteria in the genera Pectobacterium and Dickeya are of great agricultural importance, and an investigation of the virulence of these pathogens could facilitate improvements in agricultural practices, thus benefiting farmers, the potato industry and consumers.


Maintenance or emergence of chronic phase secondary cytotoxic T lymphocyte responses after loss of acute phase immunodominant responses does not protect SIV-infected rhesus macaques from disease progression.
The simian immunodeficiency virus- (SIV-) infected rhesus macaque is the preferred animal model for vaccine development, but the correlates of protection in this model are not completely understood. In this paper, we document the cytotoxic T lymphocyte (CTL) response to SIV and its effects on viral evolution in an effort to identify events associated with disease progression regardless of MHC allele expression. We observed the evolution of epitopes targeted by CTLs in a group of macaques that included long-term nonprogressing (LTNP), slowly progressing (SP), normally progressing (NP), and rapidly progressing (RP) animals. Collectively, our data (1) identify novel CTL epitopes from an SP animal that are not restricted by known protective alleles, (2) illustrate that, in this small study, RP and NP animals accrue more mutations in CTL epitopes than in SP or LTNP macaques, and (3) demonstrate that the loss of CTL responses to immunodominant epitopes is associated with viral replication increases, which are not controlled by secondary CTL responses. These findings provide further evidence for the critical role of the primary cell-mediated immune responses in the control of retroviral infections.


A role for pancreatic polypeptide in the regulation of gastric emptying and short-term metabolic control.
Previous studies using pancreatic polypeptide (PP) infusions in humans have failed to show an effect on gastric emptying, glucose metabolism, and insulin secretion. This might be due to the use of nonhuman sequences of the peptide. The objective of this study was to use synthetic human PP to study gastric emptying rates of a solid meal and postprandial hormone secretion and glucose disposal as well as the gastric emptying rate of water. This was a single-blind study. The study was performed at a university hospital. Fourteen healthy adult subjects were studied. Infusion of saline or PP at 0.75 or 2.25 pmol/kg.min was given to eight subjects (gastric emptying of solid food), and infusion of saline or PP at 2.25 pmol/kg.min was given to six subjects (gastric emptying of water). The main outcome measures were gastric emptying of solids (scintigraphy), hunger ratings (visual analog scale), and plasma concentrations of PP, insulin, glucagon, somatostatin, glucagon-like peptide 1, glucose, and gastric emptying of plain water (scintigraphy). PP prolonged the lag phase and the half-time of emptying of the solid meal. The change in hunger rating, satiety, desire to eat after the meal, or prospective consumption was not affected. The postprandial rise in plasma glucose was prolonged by PP. The postprandial rise in insulin was also delayed by PP. PP had no significant effect on the emptying of water. PP inhibits gastric emptying of solid food and delays the postprandial rise in plasma glucose and insulin. PP is suggested to have a physiological role in the pancreatic postprandial counterregulation of gastric emptying and insulin secretion.


Suicide, serotonin, and the brain.
The involvement of impaired serotonergic functioning in the development of suicidal behavior is one of the best documented findings in biological psychiatry. It is, however, less clear in which way this dysfunction contributes to the occurrence of suicidal behavior. Correlational studies have demonstrated associations between peripheral measures of serotonergic function and characteristics such as impulsivity, disinhibition, anxiety, and/or behavioral inhibition. Postmortem and neuroimaging studies have provided insight in the localization of serotonergic dysfunction in the central nervous system. Nevertheless, results in this area of research have also been contradictory. Following a short overview of recent research findings on serotonin and suicidal behavior, this paper focuses on the involvement of the prefrontal cortex of the brain in the development of suicidal behavior and on the role of serotonin in its executive functions. Based on these considerations, suggestions for future research are discussed.


Autophagy and ubiquitin-mediated proteolysis may not be involved in the degradation of spermatozoon mitochondria in mouse and porcine early embryos.
The mitochondrial genome is maternally inherited in animals, despite the fact that paternal mitochondria enter oocytes during fertilization. Autophagy and ubiquitin-mediated degradation are responsible for the elimination of paternal mitochondria in Caenorhabditis elegans; however, the involvement of these two processes in the degradation of paternal mitochondria in mammals is not well understood. We investigated the localization patterns of light chain 3 (LC3) and ubiquitin in mouse and porcine embryos during preimplantation development. We found that LC3 and ubiquitin localized to the spermatozoon midpiece at 3 h post-fertilization, and that both proteins were colocalized with paternal mitochondria and removed upon fertilization during the 4-cell stage in mouse and the zygote stage in porcine embryos. Sporadic paternal mitochondria were present beyond the morula stage in the mouse, and paternal mitochondria were restricted to one blastomere of 4-cell embryos. An autophagy inhibitor, 3-methyladenine (3-MA), did not affect the distribution of paternal mitochondria compared with the positive control, while an autophagy inducer, rapamycin, accelerated the removal of paternal mitochondria compared with the control. After the intracytoplasmic injection of intact spermatozoon into mouse oocytes, LC3 and ubiquitin localized to the spermatozoon midpiece, but remnants of undegraded paternal mitochondria were retained until the blastocyst stage. Our results show that paternal mitochondria colocalize with autophagy receptors and ubiquitin and are removed after in vitro fertilization, but some remnants of sperm mitochondrial sheath may persist up to morula stage after intracytoplasmic spermatozoon injection (ICSI).