Phenetic and genetic structure of tsetse fly populations (Glossina palpalis palpalis) in southern Ivory Coast.
Sleeping sickness, transmitted by G. p. palpalis, is known to be present in the Ivory Coast. G. p. palpalis has recently been reported to occur in several places within the town of Abidjan, including: (i) the Banco forest, (ii) the Abobo Adjamé University campus and (iii) the zoological park. Could these three places be treated sequentially, as separate tsetse populations, or should they be taken as one area comprising a single, panmictic population? The amount of gene flow between these places provides strategic information for vector control. It was estimated by the use of both microsatellite DNA and morphometric markers. The idea was to assess the interest of the faster and much less expensive morphometric approach in providing relevant information about population structure. Thus, to detect possible lack of insect exchange between these neighbouring areas of Abidjan, we used both genetic (microsatellite DNA) and phenetic (geometric morphometrics) markers on the same specimens.Using these same markers, we also compared these samples with specimens from a more distant area of south Ivory Coast, the region of Aniassué (186 km north from Abidjan). Neither genetic nor phenetic markers detected significant differentiation between the three Abidjan G. p. palpalis samples. Thus, the null hypothesis of a single panmictic population within the city of Abidjan could not be rejected, suggesting the control strategy should not consider them separately. The markers were also in agreement when comparing G. p. palpalis from Abidjan with those of Aniassué, showing significant divergence between the two sites. Both markers suggested that a successful control of tsetse in Abidjan would require the three Abidjan sites to be considered together, either by deploying control measures simultaneously in all three sites, or by a continuous progression of interventions following for instance the "rolling carpet" principle. To compare the geometry of wing venation of tsetse flies is a cheap and fast technique. Agreement with the microsatellite approach highlights its potential for rapid assessment of population structure.


Analysis of 31P NMR spectra of enzyme-bound reactants and products of adenylate kinase using density matrix theory of chemical exchange.
31P NMR spectra of equilibrium mixtures of enzyme-bound reactants and products of the adenylate kinase reaction (formula; see text) were analyzed by using computer simulations based on density matrix theory of chemical exchange. Since adenylate kinase has the unique feature that the reactants in the reverse direction are both ADP molecules, which are indistinguishable off the enzyme, the density matrix equations are formulated for the ABC + D in equilibrium A'B' + A"B" exchange appropriate for the reaction, in which the interchange of A'B' and A"B" is explicitly introduced. It is shown that the consideration of this interchange is essential to explain the experimentally observed line shapes. By comparison of the computer-simulated spectra with various values for the rates of the exchange with the experimental spectra for porcine adenylate kinase at pH 7.0 and T = 4 degrees C, the following characteristic rates were determined: interconversion rates, 375 +/- 30 s-1 (ATP formation) and 600 +/- 50 s-1 (ADP formation); interchange rates of donor and acceptor ADP's, 100 +/- 30 s-1 (in the presence of optimal Mg2+ concentration), 1500 +/- 100 s-1 (in the absence of Mg2+). It is shown that under the conditions of the experiments the interchange rate is the lower limit of the dissociation rate of ADP (or MgADP from the acceptor site if Mg2+ was present) from the enzyme complexes. The significance of these interchange rates and their values relative to the interconversion rates is discussed with special reference to the role of the Mg2+ ion in the differentiation of the two nucleotide binding sites on adenylate kinase.


[Professional liability of veterinary practitioners (author's transl)].
There are two spheres of professional liability of veterinary practitioners, in which claims can be made on these practitioners in their quality of insured. These are their liability for services and their liability for products. In both fields the issue is one of the care with which veterinary drugs and vaccines are used in an animal or group of animals respectively. As data on the subject are virtually absent in the literature, experience will have to provide the basis. In jurisdiction in the Netherlands, recourse is frequently had to Section 1401 of the Civil Code where services are concerned. Liability for products is marked by a line adopted by the Council of Ministers of the European Economic Community. It can be concluded that improvement of uniformity in the field in question may be achieved by lengthy discussion. In assessing claims for damages, however, each case will have to be judged on its own merits.


[Kleptomania in frontal lobe lesion].
A case of a kleptomaniac with frontal lobe dysfunction is presented. Kleptomania is related to the obsessive-compulsive spectrum disorders and the affective spectrum disorders. In obsessive-compulsive spectrum disorders neuroimaging and neuropsychological tasks have revealed abnormal functioning in the frontal brain which also could be related to kleptomania. Consolidated findings from animal and human studies have implied central serotonergic transmission in the genesis of obsessive-compulsive spectrum disorders and affective spectrum disorders. Altogether, these results suggest that kleptomania, like other disorders of the above mentioned spectrums, could have an abnormality in serotonergic transmission in common.


Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction.
Oxidative stress is known to be a major mechanism of endothelial dysfunction, which plays a key role in the development of cardiovascular disease. Although uric acid is one of the most important antioxidants, recent studies have suggested that uric acid may have a causal role in endothelial dysfunction. In order to understand the paradoxical association of uric acid with oxidative stress and vascular disease, we investigated whether uric acid induced oxidative stress in human vascular endothelial cells. We also examined whether uric acid-induced changes in redox status were related to aging and death of endothelial cells or an activation of local renin-angiotensin system, another mediator of endothelial dysfunction. Endothelial senescence and apoptosis were evaluated by senescence-associated beta-galactosidase staining and annexin V-propidium iodide staining in primary isolated human umbilical vein endothelial cells (HUVECs). Production of reactive oxygen species was assessed by dichlorofluorescein diacetate staining. mRNA expression of angiotensinogen, angiotensin-converting enzyme and the receptors of angiotensin II was evaluated by real-time PCR, and angiotensin II levels were measured in uric acid-stimulated HUVECs. Uric acid-induced senescence and apoptosis in HUVECs at concentrations more than 6 and 9 mg/dl, respectively. Uric acid-induced alterations in cell proliferation, senescence and apoptosis were blocked by probenecid, enalaprilat or telmisartan. Uric acid significantly increased production of reactive oxygen species beginning at 5 min, and uric acid-induced senescence and apoptosis of HUVECs were ameliorated by N-acetylcysteine or tempol. Uric acid also upregulated the expression of angiotensinogen, angiotensin-converting enzyme and angiotensin II receptors and increased angiotensin II levels, which was ameliorated with tempol. Uric acid-induced aging and death of human endothelial cells are medicated by local activation of oxidative stress and the renin-angiotensin system, which provides a novel mechanism of uric acid-induced endothelial dysfunction. Therapies targeting uric acid maybe beneficial in cardiovascular disease.


Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation.
Gefitinib (Iressa, ZD1839), a quinazoline tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR), is approved for patients with advanced non-small cell lung cancer (NSCLC) in several countries including Japan. However, the mechanism of drug sensitivity to gefitinib is not fully understood. In this study, we examined the molecular basis of sensitivity to gefitinib using nine human lung cancer cell lines derived from NSCLC. PC9 was the most sensitive to gefitinib of the nine NSCLC cell lines when assayed either by colony formation or MTS assays. The various cell lines expressed different levels of EGFR, HER2, HER3, and HER4, but there was no correlation between levels of EGFR and/or HER2 expression and drug sensitivity. Phosphorylation of EGFR, protein kinase B/AKT (Akt), and extracellular signal-regulated kinase (ERK) 1/2 was inhibited by much lower concentration of gefitinib in PC9 cells than in the other eight cell lines under exponential growing conditions. About 80% of cell surface EGFR in PC-9 was internalized within 10 min, whereas only about 30-50% of the cell surface EGFR was internalized in more drug-resistant cell lines in 15-60 min. The present study is the first to demonstrate that sensitivity to growth inhibition by gefitinib in NSCLC cell lines under basal growth condition is associated with dependence on Akt and ERK1/2 activation in response to EGFR signaling for survival and proliferation and also that drug sensitivity may be related to the extent of EGF-induced down-regulation of cell surface EGFR.


The role of curative radiotherapy in the treatment of lung cancer.
From 1963-1974, 141 patients with lung cancer were treated with curative intent in the A. Maxwell Evans Clinic in Vancouver. The clinical presentation, age and sex distribution, histology, and reasons for surgery not being carried out are examined. The results of this treatment are presented. An attempt has been made to isolate a group of patients who have a better prognosis so that treatment selection can be improved. Hemoptysis, cough, dyspnea, and incidental finding on routine chest x-ray were the most common manner of presentation. Thirty-four percent of the patients were over 70 years of age and 13% were women. The crude overall three- and five-year survival rates were 18 and 10% (19 and 9% in the men, 17 and 14% in the women). Patients presenting with dyspnea had a better survival than those presenting with cough and hemoptysis. Patients with lesions less than 3 cm in diameter had a 28% three-year survival, compared with 14% for lesions greater than 5 cm in diameter. The three- and five-year survival rates in patients over 70 years of age were 23 and 17% respectively. The response to treatment and the survival was better in the patients with squamous cell carcinoma. Twenty-two percent were alive at three years and 12% at five years as compared with 9 and 5% for other histologies. Fifty-four percent of the 35 patients with a complete response and with squamous cell carcinoma were alive at three years, compared with only 8% of the 12 patients with other histologies who showed a complete response.


[Medication reconciliation: a hell of a job].
Transitions of care pose a risk to medication safety. To reduce patient harm, medication reconciliation is advised. However, implementation of medication reconciliation is difficult due to time constraints. We present two female patients aged 82 and 84 years. In both women, unintentional discrepancies arose, went undetected and led to patient harm. Accurate information transfer is essential for continuity of patient care. Medication reconciliation comprises four steps, i.e. verification (identify discrepancies), clarification (check the collected list), reconciliation (document the reason for medication changes) and transfer (communicate the updated list). This article discusses the steps of medication reconciliation and those medication errors that arise during a patient's transfer from the home setting to hospitalization or a clinic visit. We show that medication reconciliation is not merely an administrative task. As the patient is the only constant factor in health care, patient participation is essential.


Nasogastric feeding practice in intensive care units: a study.
This study examined the practice of nasogastric feeding on one intensive care unit (ICU). Data collection took place over 135 feeding days on 26 patients who met specified criteria. A generally inconsistent approach to nasogastric feeding was discovered. Some patients received considerably more calories than required while others received significantly fewer. Calories were also over-prescribed, contrary to the findings of other studies. Despite over-prescribing, patients either received their prescribed calories or high percentages of their prescribed calories at levels higher than those previously reported.


Localization and DNA sequence around the initiation site of ribosomal RNA transcription in Physarum polycephalum.
We have used S1 nuclease to map the initiation site of ribosomal RNA transcription in the acellular slime mold Physarum polycephalum, and we have determined the sequence of 1011 nucleotides surrounding the start site. Consistent with others' observations, there is little homology with the comparable region of other species. As predicted by previous restriction mapping, direct repeats roughly 30 base pairs in length are present upstream of the initiation site and a 148 base pair duplication occurs in the external transcribed spacer. The results also suggest the presence of a processing site within the external transcribed spacer of the ribosomal transcription unit.


Effects of Testosterone and Evoked Resistance Exercise after Spinal Cord Injury (TEREX-SCI): study protocol for a randomised controlled trial.
Individuals with spinal cord injury (SCI) are at a lifelong risk of obesity and chronic metabolic disorders including insulin resistance and dyslipidemia. Within a few weeks of injury, there is a significant decline in whole body fat-free mass, particularly lower extremity skeletal muscle mass, and subsequent increase in fat mass (FM). This is accompanied by a decrease in anabolic hormones including testosterone. Testosterone replacement therapy (TRT) has been shown to increase skeletal muscle mass and improve metabolic profile. Additionally, resistance training (RT) has been shown to increase lean mass and reduce metabolic disturbances in SCI and other clinical populations. 26 individuals with chronic, motor complete SCI between 18 and 50 years old were randomly assigned to a RT+TRT group (n=13) or a TRT group (n=13). 22 participants completed the initial 16-week training phase of the study and 4 participants withdrew. 12 participants of the 22 completed 16 weeks of detraining. The TRT was provided via transdermal testosterone patches (4-6 mg/day). The RT+TRT group had 16 weeks of supervised unilateral progressive RT using surface neuromuscular electrical stimulation with ankle weights. This study will investigate the effects of evoked RT+TRT or TRT alone on body composition (muscle cross-sectional area, visceral adipose tissue, %FM) and metabolic profile (glucose and lipid metabolism) in individuals with motor complete SCI. Findings from this study may help in designing exercise therapies to alleviate the deterioration in body composition after SCI and decrease the incidence of metabolic disorders in this clinical population. The study is currently approved by the McGuire VA Medical Center and Virginia Commonwealth University. All participants read and signed approved consent forms. Results will be submitted to peer-reviewed journals and presented at national and international conferences. Pre-result, NCT01652040.


Generation of a Quantitative Luciferase Reporter for Sox9 SUMOylation.
Sox9 is a master transcription factor for chondrogenesis, which is essential for chondrocyte proliferation, differentiation, and maintenance. Sox9 activity is regulated by multiple layers, including post-translational modifications, such as SUMOylation. A detection method for visualizing the SUMOylation in live cells is required to fully understand the role of Sox9 SUMOylation. In this study, we generated a quantitative reporter for Sox9 SUMOylation that is based on the NanoBiT system. The simultaneous expression of Sox9 and SUMO1 constructs that are conjugated with NanoBiT fragments in HEK293T cells induced luciferase activity in SUMOylation target residue of Sox9-dependent manner. Furthermore, the reporter signal could be detected from both cell lysates and live cells. The signal level of our reporter responded to the co-expression of SUMOylation or deSUMOylation enzymes by several fold, showing dynamic potency of the reporter. The reporter was active in multiple cell types, including ATDC5 cells, which have chondrogenic potential. Finally, using this reporter, we revealed a extracellular signal conditions that can increase the amount of SUMOylated Sox9. In summary, we generated a novel reporter that was capable of quantitatively visualizing the Sox9-SUMOylation level in live cells. This reporter will be useful for understanding the dynamism of Sox9 regulation during chondrogenesis.


Dose optimisation during imaging in radiotherapy.
The desire to increase the precision in radiotherapy delivery has led to the development of advanced imaging systems such as amorphous silicon (a-Si)-based electronic portal imaging, and kV and MV cone beam CT. These are used prior to the delivery of radiation to visualise the organ to be treated and to ensure that the patient setup and treatment delivery are accurate. However, little attention has been given to the dose received by adjacent normal tissues during these imaging procedures. Though these doses are very small compared to the dose delivered during radiotherapy, the involvement of normal tissues and the concern that these could increase the probability of stochastic effect, mainly the induction of secondary malignancy, cannot be ignored. This article reviews some work on the doses received during imaging in radiotherapy and the methods to optimise the same.


Attaining higher goals in HIV treatment: the central importance of adherence.
In recent years, advances in HIV therapeutics have changed the nature of HIV/AIDS disease, so that it has now assumed some of the characteristics of a 'chronic' disease. Several factors have, however, qualified these advances. Social, economic, and clinical variables have confounded universal therapeutic success. Access to the highly active antiretroviral therapy is limited among marginalized populations, such as the homeless, or absent in many nations that have poor resources. In addition, study populations are often not fully representative of those actually cared for in clinical practice, who may respond differently to the study medications. Moreover, physiologic differences between patients may alter drug plasma levels, resulting in varying efficacy levels in different patients. Finally, and crucial among determinants of effective therapy, is a patient's level of adherence to the antiretroviral regimen. The magnitude of 'error-prone' viral replication makes resistance to antiretroviral agents invariable. In the presence of partially suppressive therapy, viral replication will select for viral variants with resistance mutations. Therefore, potent and continuous suppressive therapy for the duration of viral replicative capability is necessary for therapy to be effective. Factors that have an impact on adherence include characteristics of the treatment regimen, of patients and clinicians, and of the clinical setting. Successful adherence to therapeutic regimens is the responsibility of clinicians as well as patients. Many patient- and clinician-focused strategies and interventions that can improve adherence exist. The simplification of current antiviral regimens, without the loss of potency, is essential to achieving the goal of complete adherence. Maximizing the long-term benefit of highly active antiretroviral therapy requires knowledge of the technical and biologic aspects of HIV therapeutics, but necessitates an understanding of the behavioral aspects of therapeutics as well.


Particle size dependence of the ionic diffusivity.
Diffusion constants are typically considered to be independent of particle size with the benefit of nanosizing materials arising solely from shortened transport paths. We show that for materials with one-dimensional atomic migration channels, the diffusion constant depends on particle size with diffusion in bulk being much slower than in nanoparticles. This model accounts for conflicting data on LiFePO(4), an important material for rechargeable lithium batteries, specifically explaining why it functions exclusively on the nanoscale.


External beam radiation therapy for tracheobronchial amyloidosis.
Tracheobronchial amyloidosis is a rare form of primary amyloidosis. There have been no regimens for treatment of this disease that have proven to be effective. There have been case reports of external beam radiation therapy (EBRT) providing marked improvement in symptoms and the appearance of lesions. We report a series of seven consecutive patients who were treated with EBRT. All patients with tracheobronchial amyloidosis were identified who had received EBRT at Mayo Clinic, Rochester, MN. A retrospective chart review was performed. Data were collected including symptoms, method of diagnosis, treatments, result of treatments, and side effects. All patients received 20 Gy of radiation in 10 fractions. All patients had a favorable response to treatment ranging from symptom relief to a decrease in the frequency of pulmonary infections and objective improvement in pulmonary function. The time to subjective improvement ranged from 1 month to 1 year from the completion of EBRT. Grade 1 esophagitis developed in four patients, and grade 2 esophagitis developed in one patient. Grade 2 pneumonitis that resolved after 10 days of treatment with antibiotics and corticosteroids developed in one patient. FEV(1) was the most consistently used method of objective follow-up, and three of seven patients showed improvement. Follow-up ranged from 10 to 69 months (median, 40 months). The recurrence of asymptomatic endobronchial narrowing requiring no additional treatment was noted on bronchoscopy in one patient after 17 months. Tracheobronchial amyloidosis has been difficult to treat due to the limitations of treatment, recurrence, and complications. EBRT appears to be safe and can provide symptomatic as well as objective improvement.


Human TSC-associated renal angiomyolipoma cells are hypersensitive to ER stress.
Tuberous sclerosis complex (TSC), an inherited tumor predisposition syndrome associated with mutations in TSC1 or TSC2, affects ∼1 in 6,000 individuals. Eighty percent of TSC patients develop renal angiomyolipomas, and renal involvement is a major contributor to patient morbidity and mortality. Recent work has shown that mammalian target of rapamycin complex 1 (mTORC1) inhibition caused angiomyolipoma shrinkage but that this treatment may cause cytostatic not a cytotoxic effect. Endoplasmic reticulum (ER) stress can develop in TSC-associated cells due to mTORC1-driven protein translation. We hypothesized that renal angiomyolipoma cells experience ER stress that can be leveraged to result in targeted cytotoxicity. We used immortalized human angiomyolipoma cells stably transfected with empty vector or TSC2 (encoding tuberin). Using cell number quantification and cell death assays, we found that mTORC1 inhibition with RAD001 suppressed angiomyolipoma cell proliferation in a cytostatic manner. Angiomyolipoma cells exhibited enhanced sensitivity to proteasome inhibitor-induced ER stress compared with TSC2-rescued cells. After proteasome inhibition with MG-132, Western blot analyses showed greater induction of C/EBP-homologous protein (CHOP) and more poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavage, supporting ER stress-induced apoptosis. Live cell numbers also were decreased and cell death increased by MG-132 in angiomyolipoma cells compared with TSC2 rescued. Intriguingly, while pretreatment of angiomyolipoma cells with RAD001 attenuated CHOP and BiP induction, apoptotic markers cleaved PARP and caspase-3 and eukaryotic translation initiation factor 2α phosphorylation were increased, along with evidence of increased autophagy. These results suggest that human angiomyolipoma cells are uniquely susceptible to agents that exacerbate ER stress and that additional synergy may be achievable with targeted combination therapy.


The project P.A.T.H.S. in Hong Kong--lessons learned and implications for positive youth development programs.
The Project P.A.T.H.S. is a positive youth development program which attempts to promote holistic development of junior secondary schools in Hong Kong. It is ground breaking in terms of the number of schools participating in the project and financial resources injected into the project. Based on the experiences gained from the implementation of the project and evaluation data collected from 2005 to 2011, several issues pertinent to the development of positive youth development programs in the Chinese culture are discussed. These issues include complexity of program development, importance of training, identification of factors governing program implementation, need for evaluation, and promotion of sustainability of the program in the long run.


Inhibiting ventilatory evaporation produces an adaptive increase in cutaneous evaporation in mourning doves Zenaida macroura.
We tested the hypothesis that birds can rapidly change the conductance of water vapor at the skin surface in response to a changing need for evaporative heat loss. Mourning doves (Zenaida macroura) were placed in a two-compartment chamber separating the head from the rest of the body. The rate of cutaneous evaporation was measured in response to dry ventilatory inflow at three ambient temperatures and in response to vapor-saturated ventilatory inflow at two ambient temperatures. At 35 degrees C, cutaneous evaporation increased by 72 % when evaporative water loss from the mouth was prevented, but no increase was observed at 45 degrees C. For both dry and vapor-saturated treatments, cutaneous evaporation increased significantly with increased ambient temperature. Changes in skin temperature made only a minor contribution to any observed increase in cutaneous evaporation. This indicates that Z. macroura can effect rapid adjustment of evaporative conductance at the skin in response to acute change in thermoregulatory demand.


Disc space narrowing as a new risk factor for vertebral fracture: the OFELY study.
In a previous cross-sectional analysis, we found a positive association between disc space narrowing (DSN) and vertebral fracture. The aim of the present study was to analyze prospectively the risk of vertebral and nonvertebral fractures in women with spine osteoarthritis (OA). Using radiographs, spine OA was evaluated in 634 postmenopausal women from the OFELY (Os des Femmes de Lyon) cohort (mean+/-SD age 61.2+/-9 years). Prevalence and severity of spine OA were assessed by scoring osteophytes and DSN. Incidental clinical fractures were prospectively registered during annual followup, and vertebral fractures were evaluated by radiography every 4 years. During an 11-year followup, fractures occurred in 121 women, including 42 with vertebral fractures. No association was found between osteophytes and the risk of fracture. In contrast, DSN was associated with an increased risk of vertebral fractures but not of nonvertebral fractures. After adjusting for confounding variables, the presence of DSN was associated with a marked increased risk of vertebral fractures, with an odds ratio of 6.59 (95% confidence interval 1.36-31.9). In addition, 95% of incident vertebral fractures were located above the disc with the most severe narrowing. This longitudinal study shows that, despite a higher bone mineral density (BMD), women with spine OA do not have a reduced risk of fracture and that DSN is significantly associated with vertebral fracture risk. The location of DSN and of incident vertebral fractures suggests that disc degeneration impairs the biomechanics of the above spine, which leads to the increased risk of vertebral fractures, independent of BMD. We suggest that DSN is a newly identified risk factor for vertebral fracture that should be taken into consideration when assessing vertebral fracture risk in postmenopausal women.


Degradation of rhodamine B/phenol mixtures in water by sun-like excitation of a Bi2 WO6-TiO2 photocatalyst.
Bi2 WO6 and Bi2 WO6-TiO2 (5% molar Ti) nano-heterostructures were synthesized by a hydrothermal method. The properties of the synthesized catalysts were characterized, having high photoactivity for Rhodamine B degradation under sun-like illumination, explained by a synergetic mechanism previously proposed through UV and visible induced processes, in which the photosensitization effect of Rhodamine B is considered. We now report that using Phenol, a molecule which does not lead the photosensitization process, the photoactivity decreased considerably, thus emphasizing how important is the model molecule selected as degradation substrate for evaluating the photoactivity. The photocatalytic properties of the synthesized catalysts have been evaluated by exposing a mixture of Rhodamine B and Phenol in water, to different illumination conditions. It can be confirmed that the photoinduced mechanism via the photosensitization of Rhodamine B is a key factor responsible for the increase on the photocatalytic activity showed by the Bi2 WO6-TiO2 compound and that the degradation mechanism of Rhodamine B is not changed by the simultaneous presence of other transparent substrate as Phenol.


alpha 2-Adrenergic receptor regulation of ion transport in rabbit ileum.
Catecholamines are known to decrease short-circuit current (Isc), stimulate NaCl absorption, and inhibit HCO3 secretion in rabbit ileal mucosa in vitro. These effects appear to be mediated by alpha-adrenergic receptors because they are partially blocked by phentolamine and not by propranolol. To further characterize this receptor system, we determined the interactions of epinephrine (Epi) with alpha-subtype-selective antagonists. Prazosin (PZ), a specific alpha 1-antagonist, did not alter the Epi dose-response curve at concentrations up to 10(-5) M. Yohimbine (YO), a specific alpha 2-antagonist, completely inhibited the Epi effect on Isc. At 10(-5) M, YO increased by 70-fold the concentration of Epi required to produce a half-maximal effect (ED50; from 1.4 X 10(-7) M to 10(-5) M). YO and PZ by themselves had no significant effect on Isc in concentrations up to 10(-5) M. Clonidine, a specific alpha 2-agonist, decreased Isc with an ED50 similar to that of Epi; its effect was blocked by YO but not by PZ. Two alpha 1-selective agonists, methoxamine and phenylephrine, only caused a decrease in Isc in doses greater than 10(-5) M. This effect was reversed by YO but not by PZ. The effects of YO and PZ on Epi-modified Cl fluxes were also determined. YO completely aborted the effects of Epi on net Cl flux. No significant effects were seen with PZ. We conclude that the effects of Epi on ileal ion transport are mediated by a specific alpha 2-adrenergic receptor present in ileal mucosa and that no physiologic alpha 1-receptor function can be demonstrated.


Human papillomavirus-associated early vulvar neoplasia investigated by in situ hybridization.
Of 21 consecutive cases of early vulvar neoplasia studied at the Istituto Nazionale Tumori of Milan, 62% appeared to be related to papillomavirus infection. This conclusion is the result of the present study by in situ hybridization with DNA probes of human papillomavirus (HPV) 6/11, 16, and 18 and of previous ultrastructural and immunohistochemical investigations. The proportion of cases associated with HPV was 78.5% for those (11/14) with histologic evidence of viral infection and 33% for those without (2/6). HPV 16 was detected in all cases that were positive by in situ hybridization except for one, which showed HPV 6/11 DNA. In one case there was a mixed triple infection for HPV 6/11, 16, and 18. The patient who was positive for HPV 6/11 had a giant condyloma associated with an inguinal lymph node containing a metastatic well-differentiated squamous cell carcinoma. Three cases were positive for papillomavirus internal capsid species-nonspecific antigen (PV-Ag) (with ultrastructural evidence of virions in one of them) and were negative for HPV-DNA hybridization. They appeared to be infected with a type of HPV not identified by the available probes. Three cases, and two sites of two other cases with double infection, were HPV-DNA-positive and PV-Ag-negative. They illustrate the limitation of immunohistochemical investigation in cases with high-grade intraepithelial neoplasia. Six cases of verrucous carcinoma of the vulva were negative for HPV DNA by in situ hybridization.


Implementation strategies for hospital-based probiotic administration in a stepped-wedge cluster randomized trial design for preventing hospital-acquired Clostridioides difficile infection.
Clostridioides difficile infection (CDI) is associated with considerable morbidity and mortality in hospitalized patients, especially among older adults. Probiotics have been evaluated to prevent hospital-acquired (HA) CDI in patients who are receiving systemic antibiotics, but the implementation of timely probiotic administration remains a challenge. We evaluated methods for effective probiotic implementation across a large health region as part of a study to assess the real-world effectiveness of a probiotic to prevent HA-CDI (Prevent CDI-55 +). We used a stepped-wedge cluster-randomized controlled trial across four acute-care adult hospitals (n = 2,490 beds) to implement the use of the probiotic Bio-K + ® (Lactobacillus acidophilus CL1285®, L. casei LBC80R® and L. rhamnosus CLR2®; Laval, Quebec, Canada) in patients 55 years and older receiving systemic antimicrobials. The multifaceted probiotic implementation strategy included electronic clinical decision support, local site champions, and both health care provider and patient educational interventions. Focus groups were conducted during study implementation to identify ongoing barriers and facilitators to probiotic implementation, guiding needed adaptations of the implementation strategy. Focus groups were thematically analyzed using the Theoretical Domains Framework and the Consolidated Framework of Implementation Research. A total of 340 education sessions with over 1,800 key partners and participants occurred before and during implementation in each of the four hospitals. Site champions were identified for each included hospital, and both electronic clinical decision support and printed educational resources were available to health care providers and patients. A total of 15 individuals participated in 2 focus group and 7 interviews. Key barriers identified from the focus groups resulted in adaptation of the electronic clinical decision support and the addition of nursing education related to probiotic administration. As a result of modifying implementation strategies for identified behaviour change barriers, probiotic adherence rates were from 66.7 to 75.8% at 72 h of starting antibiotic therapy across the four participating acute care hospitals. Use of a barrier-targeted multifaceted approach, including electronic clinical decision support, education, focus groups to guide the adaptation of the implementation plan, and local site champions, resulted in a high probiotic adherence rate in the Prevent CDI-55 + study.


The Nigerian national blindness and visual impairment survey: Rationale, objectives and detailed methodology.
Despite having the largest population in Africa, Nigeria has no accurate population based data to plan and evaluate eye care services. A national survey was undertaken to estimate the prevalence and determine the major causes of blindness and low vision. This paper presents the detailed methodology used during the survey. A nationally representative sample of persons aged 40 years and above was selected. Children aged 10-15 years and individuals aged <10 or 16-39 years with visual impairment were also included if they lived in households with an eligible adult. All participants had their height, weight, and blood pressure measured followed by assessment of presenting visual acuity, refractokeratomery, A-scan ultrasonography, visual fields and best corrected visual acuity. Anterior and posterior segments of each eye were examined with a torch and direct ophthalmoscope. Participants with visual acuity of < = 6/12 in one or both eyes underwent detailed examination including applanation tonometry, dilated slit lamp biomicroscopy, lens grading and fundus photography. All those who had undergone cataract surgery were refracted and best corrected vision recorded. Causes of visual impairment by eye and for the individual were determined using a clinical algorithm recommended by the World Health Organization. In addition, 1 in 7 adults also underwent a complete work up as described for those with vision < = 6/12 for constructing a normative data base for Nigerians. The field work for the study was completed in 30 months over the period 2005-2007 and covered 305 clusters across the entire country. Concurrently persons 40+ years were examined to form a normative data base. Analysis of the data is currently underway. The methodology used was robust and adequate to provide estimates on the prevalence and causes of blindness in Nigeria. The survey would also provide information on barriers to accessing services, quality of life of visually impaired individuals and also provide normative data for Nigerian eyes.


Ion-pair high-performance liquid chromatography of purine compounds in the small intestinal mucosa of children with coeliac disease.
Isocratic methods are described for the separation of purine compounds in specimens of jejunal mucosa available by peroral biopsy from patients with coeliac disease. The first mode provided separation of both the ionic nucleoside monophosphates and the non-ionic nitrogen bases and nucleosides. The second mode was applicable to analyses of the nucleoside mono-, di- and triphosphates only. These chromatographic procedures were carried out with tetrabutylammonium phosphate as an ion-pair modifier and different concentrations of acetonitrile in the mobile phase. The modes are flexible in that they permit the optimization of the separation of these compounds according to the purpose of the investigation. The results of studies on purine metabolite patterns in coeliac mucosa are discussed.


CXCR2 Antagonist MK-7123. A Phase 2 Proof-of-Concept Trial for Chronic Obstructive Pulmonary Disease.
An antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD). To assess the efficacy, safety, and tolerability of three dose levels of MK-7123, compared with placebo, in patients with moderate to severe COPD. This 6-month, double-blind study randomized patients with moderate to severe COPD (already on standard therapy) to daily MK-7123 at 10, 30, or 50 mg or placebo. The primary endpoint was change from baseline in post-bronchodilator FEV1. A total of 616 patients (71% male; mean age, 63 yr; 45% current smokers; baseline FEV1 [SD], 1.43 L [0.45]; mean FEV1 percent predicted, 43.9%) were randomized. Only MK-7123 50 mg led to significant improvement in FEV1 over placebo (mean difference [SE], 67 ml [32]). Reduced sputum neutrophil count was observed among the 122 patients examined; P = 0.003 (3 mo) and P = 0.092 (6 mo) (MK-7123 50 mg vs. placebo). The stratum of current smokers, but not that of nonsmokers, showed significant improvement versus placebo in FEV1 (168 ml) and time-to-first exacerbation, and showed numerical improvement in St. George's Respiratory Questionnaire for COPD score. MK-7123 caused a dose-dependent decrease in absolute neutrophil count (ANC) and reduced inflammatory biomarkers matrix metallopeptidase-9 and myeloperoxidase in plasma and sputum; ANC lower than 1.5 × 10(9)/L led to discontinuations with higher doses of MK-7123 (18% in the MK-7123 50-mg group vs. 1% in placebo). Plasma C-reactive protein and fibrinogen increased with MK-7123 treatment. Rates of infections at 6 months were similar in all groups. Treatment with MK-7123 50 mg versus placebo led to significant improvement in FEV1 in patients with COPD, suggesting clinically important antiinflammatory effects with CXCR2 antagonism, although dose-related discontinuations were observed because of ANC decreases with MK-7123. Greater response was observed in smokers versus ex-smokers. Clinical trial registered with www.clinicaltrials.gov (NCT 01006616).


Acoustic emission analysis of the effect of simulated pulpal pressure and cavity type on the tooth-composite interfacial de-bonding.
The aim of this study was to evaluate the influence of in vitro pulpal pressure and cavity type on the tooth-composite bonding interface by means of acoustic emission (AE) analysis. Classes I and II cavities on extracted third molars were prepared and assigned to four groups of seven teeth each: (1) direct composite restoration without simulated pulpal pressure (SPP) in class I cavity, (2) direct composite restoration with SPP in class I cavity, (3) direct composite restoration without SPP in class II cavity, (4) direct composite restoration with SPP in class II cavity. The teeth were restored with Filtek Z250 composite and Adper Scotchbond Multi-Purpose adhesive system (3M ESPE, St. Paul, MN, USA). AE events were recorded for 2000s during light-curing. Groups 2 and 4 were subjected to 20 cm H2O hydrostatic pressure throughout the procedures. The data were analyzed with two-way ANOVA. After the AE test, teeth were sectioned longitudinally in mesio-distal direction, the tooth-composite interface was examined using SEM. SPP in Groups 2 (4.57 ± 1.40) and 4 (3.43 ± 1.13) yielded significantly higher AE events number than those of Groups 1 (3.43 ± 1.51) and 3 (1.71 ± 0.95) where the SPP was not applied (p<0.05). The number of AE events of class I cavity in Groups 1 and 2 were significantly higher than those of class II cavity in Groups 3 and 4 (p<0.05). SEM examination showed that all groups had intact enamel-composite interface, while micro-gaps were observed at the dentin-composite interface, mainly at the pulpal floor of the cavity. The class I cavities with SPP in Group 2 showed wider gaps more frequently than class II cavities without SPP in Group 3. The SPP and class I cavity with high C-factor triggered more AE events, confirming its negative impact on the bonding interface.


Tardive dyskinesia in the treatment of schizophrenia: the findings of the Research on Asian Psychotropic Prescription Pattern (REAP) survey (2001 - 2009).
The aim of the study was to survey the frequency of tardive dyskinesia (TD) in patients with schizophrenia and its demographic and clinical correlates in selected Asian countries. A total of 6,761 hospitalized schizophrenia patients in nine Asian countries and territories were examined from 2001 to 2009. TD was evaluated as "present" or "absent" according to the clinical judgment of experienced psychiatrists. The patients' socio-demographic and clinical characteristics and the prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. The frequency of TD in the whole sample was 5.0% with wide variations between countries (0 - 14.9%). Multiple logistic regression analysis showed that the following variables were independently associated with TD: study time, study site, older age, male gender, more severe negative and extrapyramidal symptoms and less anticholinergic drugs. A generally low frequency of TD in Asian schizophrenia patients with inter-ethnic variations was recorded. It is unclear whether the low prevalence of TD compared with Western data is real or the result of it being insufficiently recognized.


AMPK activation by pterostilbene contributes to suppression of hepatic gluconeogenic gene expression and glucose production in H4IIE cells.
Pterostilbene, a bioactive component of blueberries and grapes, shows structural similarity to resveratrol, and exhibits antioxidant, anti-inflammatory, anti-cancer, hypoglycemic, and cholesterol lowering effects. Recent evidence indicates that pterostilbene is an agonist of the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR-α). Since PPAR-α agonists induce peroxisomal proliferation and fatty acid oxidation, we examined gene expression of acyl CoA oxidase (ACO) and carnitine palmitoyl transferase-1 (CPT-1). Pterostilbene treatment, at concentrations that demonstrated over 75% cell viability (20 μM, 50 μM), significantly increased gene expression of ACO, CPT-1, and PPAR-α. Pterostilbene treatment (50 μM) also demonstrated potent activation of AMP-activated kinase (AMPK), compared to AICAR (0.5 mM) or metformin (2 mM), consistent with upregulation in fatty acid oxidation gene expression. Since AMPK activators mimic the actions of insulin by repressing hepatic gluconeogenesis, we examined pterostilbene's effects on hepatic gluconeogenic gene expression. Pterostilbene treatment significantly repressed dexamethasone-induced phosphoenol pyruvate carboxykinase (PEPCK) and glucose6-phosphatase (G6Pase) gene expression, and decreased glucose production in H4IIE cells. Taken together, our studies demonstrate that pterostilbene, a natural compound and PPAR-α agonist, modulate several AMPK-dependent metabolic functions. The results of the present study suggest that pterostilbene may have beneficial effects in the prevention and management of type 2 diabetes and related disorders. In this study, we found that pterostilbene activated AMP-activated kinase (AMPK) and increased the expression of fatty acid oxidation genes, including acyl CoA oxidase and carnitine palmitoyl transferase-1.


[Drug-drug interactions in nursing home patients].
Patients in nursing homes are often treated with many drugs concurrently (polypharmacy), which increases the risk of drug-drug interactions. The purpose of this study was to assess the incidence of such interactions in nursing home patients. The study was based on medication lists collected from all nursing home patients in Trondheim Municipality in the course of one day in 2010. Data from the medication lists was linked to the Norwegian interaction database, Druid. The study included 1241 nursing home patients. Patients used an average of 9.8 drugs regularly or as needed, with a variation of from 0 to 30. In all, 15 patients (1.2%) used drug combinations that are classified in Druid as «should not be combined», while 592 (47.7%) used combinations classified as «take precautions». There was a clear relationship between the number of drugs prescribed and the risk of interactions. The three most common drug combinations in the group «should not be combined» were warfarin and non-steroidal anti-inflammatory drugs, clopidogrel and proton pump inhibitors, and anti-Parkinson medication and dopamine antagonists. The incidence of serious drug-drug interactions among nursing home patients in Trondheim Municipality is low. Polypharmacy is widespread, and the incidence of drug interactions where precautions should be taken is high. As nursing home patients are a vulnerable group with respect to drug interactions, the risk of interactions should be carefully considered when treatment with a new drug is started.


Altered Hippocampal Neurogenesis during the First 7 Days after a Fluid Percussion Traumatic Brain Injury.
Traumatic brain injury (TBI) is a devastating disorder causing negative outcomes in millions of people each year. Despite the alarming number of brain injuries and the long-term detrimental outcomes that can be associated with TBI, treatment options are lacking. Extensive investigation is underway, in hopes of identifying effective treatment strategies. Among the most state-of-the-art strategies is cell replacement therapy. TBI is a seemingly good candidate for cell replacement studies because there is often loss of neurons. However, translation of this therapy has not yet been successful. It is possible that a better understanding of endogenous neurogenic mechanisms after TBI could lead to more efficacious study designs using exogenous cell replacement strategies. Therefore, this study was designed to examine the number and migration of immature neurons at 1 and 7 d after a fluid percussion TBI. The results show that the number of immature neurons increases from 7 d after a fluid percussion injury (FPI), and there is ectopic migration of doublecortin (DCX+) immature neurons into the hilar region of the dentate gyrus. These results add important data to the current understanding of the endogenous neurogenic niche after TBI. Follow-up studies are needed to better understand the functional significance of elevated neurogenesis and aberrant migration into the hilus.


A high-throughput screen for endothelial lipase using HDL as substrate.
Endothelial lipase (EL) is a 482-amino-acid protein from the triglyceride lipase gene family that uses a Ser-His-Asp triad for catalysis. Its expression in endothelial cells and preference for phospholipids rather than triglycerides are unique. Animal models in which it is overexpressed or knocked out indicate EL levels are inversely correlated with high-density lipoprotein cholesterol (HDL-C). HDL-C is commonly referred to as the good form of cholesterol because it is involved in the reverse cholesterol transport pathway, in which excess cholesterol is effluxed from peripheral tissues for excretion or reabsorption. Thus, EL inhibition in humans is expected to lead to increases in HDL levels and possibly a decrease in cardiovascular disease. To discover inhibitors of EL, a coupled assay for EL has been developed, using its native substrate, HDL. Hydrolysis of HDL by EL yields free fatty acids, which are coupled through acyl-CoA synthetase, acyl-CoA oxidase, and horseradish peroxidase to produce the fluorescent species resorufin. This assay was developed into a 5-microL, 1536-well assay format, and a high-throughput screen was executed against the GSK collection. In addition to describing the screening results, novel post-HTS mechanism-of-action studies were developed for EL and applied to 1 of the screening hits as an example.


Possible links between intestinal permeability and food processing: A potential therapeutic niche for glutamine.
Increased intestinal permeability is a likely cause of various pathologies, such as allergies and metabolic or even cardiovascular disturbances. Intestinal permeability is found in many severe clinical situations and in common disorders such as irritable bowel syndrome. In these conditions, substances that are normally unable to cross the epithelial barrier gain access to the systemic circulation. To illustrate the potential harmfulness of leaky gut, we present an argument based on examples linked to protein or lipid glycation induced by modern food processing. Increased intestinal permeability should be largely improved by dietary addition of compounds, such as glutamine or curcumin, which both have the mechanistic potential to inhibit the inflammation and oxidative stress linked to tight junction opening. This brief review aims to increase physician awareness of this common, albeit largely unrecognized, pathology, which may be easily prevented or improved by means of simple nutritional changes.


Numerical simulation and visualization of elastic waves using mass-spring lattice model.
A computer program package has been developed for simulation and visualization of two-dimensional elastic wave propagation and scattering using the mass-spring lattice model (MSLM) and, for comparison, a finite difference model. To assess the reliability of the numerical schemes, their convergence and accuracy have been analysed using the Taylor series expansion and the von Neumann analysis methods. As a result, the grid spacing-time increment combinations previously adopted in the literature have proved to be non-optimal. The optimal combinations have been found and shown to yield the most accurate results with the least computation time, particularly in the high frequency regime. Using these algorithms, a program package has been developed in Visual C++ (Microsoft, Redmond, WA) with graphic user interfaces for convenient exploration of visualized results. Numerical results have been obtained for some fundamental problems in ultrasonic testing such as plane waves incident on cracks. All numerical results have shown excellent qualitative agreements with the analytical results of the wave physics, as the reflected, diffracted, head, and Rayleigh waves have been observed. Also, for numerical results with anisotropic media, the cusps on the shear wavefronts have been observed. Finally, slight modification of the modeling method for free surfaces has led to more accurate prediction of Rayleigh waves.


Femoroacetabular impingement in skeletally immature patients: a systematic review examining indications, outcomes, and complications of open and arthroscopic treatment.
Improvements in physical examination and radiographic appreciation of symptomatic femoroacetabular impingement (FAI) has increased the focus on early diagnosis and treatment in an adolescent population. This systematic review aimed to establish specific indications, outcomes, and complications of surgical management of adolescent FAI. The Medline, Embase, and PubMed online databases were searched from inception until April 21, 2014, for English-language studies that addressed open and/or arthroscopic treatment of FAI in patients aged 10 to 19 years inclusively. The studies were systematically screened and data abstracted in duplicate, with qualitative findings presented. There were 6 eligible case series (4 with arthroscopic and 2 with open technique) and 2 conference abstracts examining 388 patients in total (435 hips), 81% of which were treated with hip arthroscopy. Overall, patients were followed up for a mean of 23.4 months postoperatively (range, 3 to 75 months). The main indication for surgery was a confirmed diagnosis of FAI with persistent pain and impaired function refractory to nonoperative interventions (activity modification, intra-articular injections, and so on). Specific contraindications included Tönnis grade 2, 3, or 4 chondral changes and acetabular dysplasia. All studies reported significant improvements in patient pain, function (e.g., no patients were "abnormally" or "severely abnormally" impaired), and satisfaction rates (84% to 100% with arthroscopic technique v 79% with open technique). Improvements also were observed in range of motion and alpha angle correction, as well as across a variety of patient-reported functional scores, with all but 7 of 388 patients (1.8%) returning to activity/sport. No major complications were reported, with only 13 of 354 hips (3.7%) treated by arthroscopy requiring revision arthroscopy for lysis of adhesions and 1 of 81 open surgical dislocation hips (1%) having asymptomatic heterotopic ossification not requiring additional management. No cases of avascular necrosis, physeal arrest or growth disturbance, or iatrogenic deformity were reported. Both arthroscopic and open surgical dislocation approaches for the treatment of adolescent FAI appear to be safe and effective options for patients with persistent pain and limited function after an appropriate trial of nonoperative therapy. Level IV, systematic review of Level IV studies.


Incorporation of AMMI stability value and grain yield in a single non-parametric index (GSI) in bread wheat.
In order to determine stable bread wheat genotypes with high grain yield via a single parameter, field experiments were conducted with 20 genotypes for 4 consecutive years in two different conditions (irrigated and rainfed) in a completely randomized block design with three replications in each environment. Combined analysis of variance showed highly significant differences for the GE interaction indicating the possibility of selection for stable entries. The results of additive main effect and multiplicative interaction (AMMI) analysis revealed 10% of total variability was justified by the GE interaction which was 2.5 times more than that of genotypes. Ordination techniques displayed high differences for the interaction principal components (IPC1, IPC2 and IPC3), exhibiting that 83% of the GE sum of squares was justified by AMMI1, AMMI2 and AMMI3, i.e., 3.77 times more than that explained by the linear regression model displaying the relative efficiency of AMMI1 model in comparison with regression model. AMMI stability value (ASV) discriminated genotypes G6, G9, G14, G15, G17 and G18 as the stable entries. As stability per se is not a desirable selection criterion, because the most stable genotypes would not necessarily give the best yield performance, hence, simultaneous consideration of grain yield and ASV in a single non-parametric index entitled: Genotype Selection Index (GSI), discriminated G6 and G17 with general adaptability and high grain yield for rainfed and irrigated conditions which was in agreement with the results of biplot analysis.


MDM-2 oncoprotein overexpression in laryngeal squamous cell carcinoma: association with wild-type p53 accumulation.
The MDM-2 gene encodes for a nuclear phosphoprotein that binds p53 and inhibits its ability to activate transcription by concealing the p53 activation domain. It has been suggested that MDM-2 overexpression might represent an alternative mechanism by which p53-mediated pathways are inactivated in human tumors. MDM-2 overexpression can be detected by immunohistochemical analysis as a result of gene amplification and/or increased mRNA expression. We studied MDM-2 gene amplification and protein overexpression in 46 and 50 cases, respectively, of laryngeal squamous cell carcinomas previously analyzed for p53 gene alterations. Not one of the cases showed MDM-2 gene amplification, whereas MDM-2 nuclear immunoreactivity was found in 17 tumors (34%). In 10 of these, coexpression of p53 protein was detectable in the absence of gene mutations in exons 5 through 9 (P = .03). Likewise, MDM-2 was also overexpressed in 18 (46%) of 39 morphologically normal mucosa samples, 15 (50%) of 30 preneoplastic lesions, and 9 (40%) of 22 cases of severe dysplasia. Finally, we found no significant correlations between MDM-2 expression (neither per se nor in association with wild-type or mutated p53), and the evaluated clinicopathologic parameters of histologic grade, lymph node status, or clinical stage. Our results suggest that MDM-2 gene amplification might not occur in laryngeal carcinomas and that MDM-2 protein overexpression might represent an alternative mechanism by which p53 is inactivated in the early stages of laryngeal cancer tumorigenesis.


Use of fractionated laser therapy for the treatment of androgenetic alopecia: a systematic review and meta-analysis.
Procedural management, including fractionated laser therapy, has been increasingly investigated for the management of androgenetic alopecia (AGA). However, no comprehensive resources exist detailing the efficacy of fractionated laser therapies used for the treatment of AGA. A systematic review investigating fractionated laser use for AGA was performed, separated into each distinct fractionated laser modality. A meta-analysis was performed to examine improvement in hair counts and hair shaft diameter. Fourteen studies were included for systematic review, which identified the use of erbium-glass, thulium, erbium-ytrrium:aluminum garnet (YAG), and carbon dioxide (CO2) fractionated laser for the treatment of AGA. In the meta-analysis, fractionated laser combination therapy showed significant improvement in hair shaft diameter (2.51, 95% CI 2.37-2.65, I2 = 90.54). Fractionated laser monotherapy alone significantly improved hair shaft diameter (2.28 95% CI 2.03-2.52, I2 = 91.20%). This effect was durable on subgroup analysis for both erbium-glass (2.36 95% CI 2.01-2.71, I2 = 92.05%) and thulium (1.61 95% CI 1.08-2.15, I2 = < 0.00%). There was no improvement in hair shaft count for any laser modality. Erbium-glass laser is an effective modality as either monotherapy or combination with topical/injectable therapies to improve hair shaft diameter in AGA.


Veganism does not reduce the risk of the metabolic syndrome in a Taiwanese cohort.
The purpose of the present study was to assess the risk of the metabolic syndrome (MS) with vegan, pescovegetarian, lactovegetarian and nonvegetarian diets in Taiwan. The design was a retrospective cohort study using secondary data analysis from a Taiwan longitudinal health check-up database provided by MJ Health Screening Center during 1996-2006. A total of 93209 participants were classified as vegans (n=1116), pescovegetarians (n=2461), lactovegetarians (n=4313) and nonvegetarians (n=85319) by food frequency list of self-administered questionnaire at baseline. The association between MS or MS components and different dietary groups was evaluated using Cox proportional-hazards regression models with adjustment for confounders. During the mean 3.75 years of follow up, a total 8006 MS incident cases occurred and the incidence of MS was 229 (95% CI, 224, 234) per 10000 person year. Compared with vegans, hazard ratios of MS for nonvegetarians, pescovegetarians, lactovegetarians were 0.75 (95% CI, 0.64, 0.88), 0.68 (95% CI, 0.55, 0.83) and 0.81 (95% CI, 0.67, 0.97) after adjusting for sex, age, education status, smoking status, drinking status, physical activity at work and leisure, respectively. As for MS components, nonvegetarians and pescovegetarians had 0.72 (95% CI, 0.62, 0.84), 0.70 (95% CI, 0.57, 0.84) times risk of developing low high density lipoprotein cholesterol (HDL-C), while nonvegetarians had 1.16 (95% CI, 1.02, 1.32) times risk of developing high fasting plasma glucose. Our data suggest that the vegan diets did not decrease the risk of metabolic syndrome compared with pescovegetarian, lactovegetarian and nonvegetarian diets in a Taiwanese cohort.


Effect of long-term use of moisturizer on skin hydration, barrier function and susceptibility to irritants.
Moisturizers are often used in the prevention and treatment of irritant contact dermatitis. The present study was to determine whether long-term daily use of a moisturizer on normal skin would affect skin barrier function, hydration state, or susceptibility to sodium lauryl sulphate. Healthy volunteers used a moisturizer on one forearm 3 times daily for 4 weeks. The other forearm served as a control. Afterwards both forearms were challenged with a patch-test of sodium lauryl sulphate. Skin barrier function was evaluated by measuring trans-epidermal water loss and skin hydration by measuring electrical capacitance. Electrical capacitance was significantly increased on the treated arm during the treatment period. After challenge with sodium lauryl sulphate, transepidermal water loss was significantly higher on the arm treated with moisturizer than on the control arm. The results suggest that long-term treatment with moisturizers on normal skin may increase skin susceptibility to irritants.


Understanding Body Language Does Not Require Matching the Body's Egocentric Map to Body Posture: A Brain Activation fMRI Study.
Body language (BL) is a type of nonverbal communication in which the body communicates the message. We contrasted participants' cognitive processing of body representations or meanings versus body positions. Participants (N = 20) were shown pictures depicting body postures and were instructed to focus on their meaning (BL) or on the position of a body part relative to the position of another part (body structural description [BSD]). We examined activation in brain areas related to the two types of body representation-body schema and BSD-as modulated by the two tasks. We presumed that if understanding BL triggers embodiment of body posture, a matching procedure between the egocentric map coding the position of one's body segments in space and time should occur. We found that BL (vs. BSD) differentially activated the angular gyrus bilaterally, the anterior middle temporal gyrus, the temporal pole, and the right superior temporal gyrus, the inferior frontal gyrus, the superior medial gyrus, and the left superior frontal gyrus. BSD (vs. BL) differentially activated the superior parietal lobule (Area 7A) bilaterally, the posterior inferior temporal gyrus, the middle frontal gyrus, and the left precentral gyrus. Sensorimotor areas were differentially activated by BSD when compared with BL. Inclusive masking showed significant voxels in the superior colliculus and pulvinar, fusiform gyrus, inferior temporal gyrus, superior temporal gyrus, the intraparietal sulcus bilaterally, inferior frontal gyrus bilaterally, and precentral gyrus. These results indicate common brain networks for processing BL and BSD, for which some areas show differentially stronger or weaker processing of one task or the other, with the precuneus and the superior parietal lobule, the intraparietal sulcus, and sensorimotor areas most related to the BSD as activated by the BSD task. In contrast, the parietal operculum, an area related to the body schema, a representation crucial during embodiment of body postures, was not activated for implicit masking or for the differential contrasts.


Stem cell mobilizating effect of heparin in patients undergoing autologous stem cell transplantation.
Adequate stem cell collection is essential for successful stem cell transplantation. Heparin enhances stem cell mobilization by competing with heparin sulfate proteoglycans. Heparin is also used as an anticoagulant before leukapheresis. Here, we evaluated the effects of heparin on stem cell mobilization in patients who underwent autologous stem cell transplantation (ASCT). We evaluated patients who underwent ASCT. Patients were divided into two groups: those who received heparin plus citrate (heparinized patients) and those who received citrate only (nonheparinized patients) for anticoagulation. Univariate and multivariate analyses were also performed. The collection efficiency 2 (CE2) for CD34+ cells was calculated and compared between heparinized and nonheparinized patients. This study included 1017 patients. There were 478 (47%) heparinized and 539 (53%) nonheparinized patients. The number of collected CD34+ cells was significantly higher in heparinized patients (P < .00001). The multivariate analyses showed that using heparin was an independent positive factor for collected CD34+ cells (adj-R2 = 0.744; F = 369.331, P < .00001). CE2 was significantly higher in heparinized patients than in nonheparinized patients (66.8% vs 52.1%; P < .00001). The rate of collecting at least 2 × 106 /kg CD34+ cells was 3.3 times higher for heparinized patients in poor mobilizers (P < .00001). Heparinized patients had significantly higher total nucleated and mononuclear cell counts (P < .00001 and <.00001, respectively). Heparin enhances stem cell collection and increases CE2. The use of heparin may reduce the need for other strategies to increase stem cell mobilization.


Quantitative in vitro to in vivo extrapolation of tissues toxicity.
Predicting repeated-dosing in vivo drug toxicity from in vitro testing and omics data gathering requires significant support in bioinformatics, mathematical modeling and statistics. We present here the major aspects of the work devoted within the framework of the European integrated Predict-IV to pharmacokinetic modeling of in vitro experiments, physiologically based pharmacokinetic (PBPK) modeling, mechanistic models of toxicity for the kidney and brain, large scale dose-response analyses methods and biomarker discovery tools. All of those methods have been applied to various extent to the drug datasets developed by the project's partners. Our approach is rather generic and could be adapted to other drugs or drug candidates. It marks a successful integration of the work of the different teams toward a common goal of predictive quantitative in vitro to in vivo extrapolation.


Localized oscillatory states in magnetoconvection.
Localized states are found in many pattern forming systems. The aim of this paper is to investigate the occurrence of oscillatory localized states in two-dimensional Boussinesq magnetoconvection. Initially considering an idealized model, in which the vertical structure of the system has been simplified by a projection onto a small number of Fourier modes, we find that these states are restricted to the low ζ regime (where ζ represents the ratio of the magnetic to thermal diffusivities). These states always exhibit bistability with another nontrivial solution branch; in other words, they show no evidence of subcritical behavior. This is due to the weak flux expulsion that is exhibited by these time-dependent solutions. Using the results of this parameter survey, we locate corresponding states in a fully resolved two-dimensional system, although the mode of oscillation is more complex in this case. This is the first time that a localized oscillatory state, of this kind, has been found in a fully resolved magnetoconvection simulation.


Factors associated with initiating someone into illicit drug injection.
Most people who inject drugs (PWID) were first initiated into injection by a current PWID. Few studies have examined PWID who assist others into drug injection. Our goal is to describe the prevalence of and risk factors for initiating someone into injection in the last 12 months. We recruited a cross-sectional sample of PWID (N=605) in California from 2011 to 2013. We examined bivariate and multivariate risk factors for initiating someone into injection with a focus on behaviors that might encourage injection initiation such as injecting in front of non-PWID, describing how to inject to non-PWID, and willingness to initiate someone into drug injection. Having initiated someone into injection was reported by 34% of PWID overall and 7% in the last 12 months. Forty-four PWID had assisted 431 people into injection in the past year. Factors independently associated with initiating someone into injection in the last 12 months were self-reported likelihood of initiating someone in the future (Adjusted Odds Ratio [AOR]=7.09; 95% Confidence Interval [CI]=3.40, 14.79), having injected another PWID in past month (AOR=4.05; 95% confidence interval [CI]=1.94, 8.47), having described how to inject to non-injectors (2.61; 95% CI=1.19, 5.71), and non-injection powder cocaine use in past month (AOR=4.97; 95% CI=2.08, 11.84) while controlling for study site. Active PWID are important in facilitating the process of drug injection uptake. Interventions to reduce initiation should include efforts to change behaviors and intentions among PWID that are associated with injection uptake among others.


A multicomponent assembly pathway contributes to the formation of acentrosomal microtubule arrays in interphase Drosophila cells.
In animal cells, centrosomes nucleate microtubules that form polarized arrays to organize the cytoplasm. Drosophila presents an interesting paradox however, as centrosome-deficient mutant animals develop into viable adults. To understand this discrepancy, we analyzed behaviors of centrosomes and microtubules in Drosophila cells, in culture and in vivo, using a combination of live-cell imaging, electron microscopy, and RNAi. The canonical model of the cycle of centrosome function in animal cells states that centrosomes act as microtubule-organizing centers throughout the cell cycle. Unexpectedly, we found that many Drosophila cell-types display an altered cycle, in which functional centrosomes are only present during cell division. On mitotic exit, centrosomes disassemble producing interphase cells containing centrioles that lack microtubule-nucleating activity. Furthermore, steady-state interphase microtubule levels are not changed by codepleting both gamma-tubulins. However, gamma-tubulin RNAi delays microtubule regrowth after depolymerization, suggesting that it may function partially redundantly with another pathway. Therefore, we examined additional microtubule nucleating factors and found that Mini-spindles, CLIP-190, EB1, or dynein RNAi also delayed microtubule regrowth; surprisingly, this was not further prolonged when we codepleted gamma-tubulins. Taken together, these results modify our view of the cycle of centrosome function and reveal a multi-component acentrosomal microtubule assembly pathway to establish interphase microtubule arrays in Drosophila.


Tackling MARCKS-PIP3 circuit attenuates fibroblast activation and fibrosis progression.
Targeting activated fibroblasts, including myofibroblast differentiation, has emerged as a key therapeutic strategy in patients with idiopathic pulmonary fibrosis (IPF). However, there is no available therapy capable of selectively eradicating myofibroblasts or limiting their genesis. Through an integrative analysis of the regulator genes that are responsible for the activation of IPF fibroblasts, we noticed the phosphatidylinositol 4,5-bisphosphate (PIP2)-binding protein, myristoylated alanine-rich C-kinase substrate (MARCKS), as a potential target molecule for IPF. Herein, we have employed a 25-mer novel peptide, MARCKS phosphorylation site domain sequence (MPS), to determine if MARCKS inhibition reduces pulmonary fibrosis through the inactivation of PI3K/protein kinase B (AKT) signaling in fibroblast cells. We first observed that higher levels of MARCKS phosphorylation and the myofibroblast marker α-smooth muscle actin (α-SMA) were notably overexpressed in all tested IPF lung tissues and fibroblast cells. Treatment with the MPS peptide suppressed levels of MARCKS phosphorylation in primary IPF fibroblasts. A kinetic assay confirmed that this peptide binds to phospholipids, particularly PIP2, with a dissociation constant of 17.64 nM. As expected, a decrease of phosphatidylinositol (3,4,5)-trisphosphate pools and AKT activity occurred in MPS-treated IPF fibroblast cells. MPS peptide was demonstrated to impair cell proliferation, invasion, and migration in multiple IPF fibroblast cells in vitro as well as to reduce pulmonary fibrosis in bleomycin-treated mice in vivo. Surprisingly, we found that MPS peptide decreases α-SMA expression and synergistically interacts with nintedanib treatment in IPF fibroblasts. Our data suggest MARCKS as a druggable target in pulmonary fibrosis and also provide a promising antifibrotic agent that may lead to effective IPF treatments.-Yang, D. C., Li, J.-M., Xu, J., Oldham, J., Phan, S. H., Last, J. A., Wu, R., Chen, C.-H. Tackling MARCKS-PIP3 circuit attenuates fibroblast activation and fibrosis progression.


Topical ocular administration using thermosensitive chitosan-glycerophosphate-PRP hydrogels for improved ocular bioavailability.
One of the difficulties in the pharmacy field is the delivery of drugs for the eyes. Topical therapy is one of the most common methods for treating eye diseases. Due to their unique properties, including biocompatibility and suitable degradation, hydrogels are appropriate for biological purposes. Platelet-rich plasma (PRP), as a designated concentration of platelets, is in a smaller volume than the plasma and is considered a rich source of growth factor that has been used in recent years, including applications in eye diseases including corneal wound healing, improvement of dry eye and post-LASIK syndrome. The present study was performed to fabricate Chitosan (CS) and glycerophosphate (GP) based hydrogels that are temperature-sensitive for PRP and investigate their effect on ocular stem cells. CS-GP-based temperature-sensitive hydrogels containing PRP were successfully fabricated using CS and GP. This hydrogel is liquid at ambient temperature and a gel at ocular temperature. Rheology, FTIR, and SEM tests assessed the properties of the hydrogels. The results of the MTT test showed that the hydrogel made with the optimal formulation was not toxic to LSC cell lines. Given this, CS-GP-based hydrogels can be applied as a biocompatible formulation in ocular medication administration with increased bioavailability at the ocular surface and topical delivery of PRP.


Neonatal growth outcomes at birth and one month postpartum following in utero exposure to antidepressant medication.
There is evidence of increasing prescription of antidepressant medication in pregnant women. This has arisen from the recognition of the importance of treating maternal depression. This must be balanced, however, with information on outcomes for infants and children exposed to antidepressants in pregnancy. The aim of the present study was to examine whether neonatal outcomes including gestational age at birth, neonatal growth outcomes at birth and then at 1 month postpartum were altered by in utero exposure to antidepressant medication using a prospective and controlled design. A prospective case-control study recruited 27 pregnant women taking antidepressant medication and 27 matched controls who were not taking antidepressant medication in pregnancy at an obstetric hospital in Melbourne, Australia. Of the 27 women taking medication, 25 remained on medication in the third trimester. A purpose-designed self-report questionnaire and the Beck Depression Inventory-II were completed in pregnancy, after birth and at one month postpartum. In addition information was collected on exposed and non-exposed infants including Apgar scores, birthweight/length/head circumference and gestational age at birth. Weight/length/head circumference was again collected at 1 month of age. Infants exposed to antidepressants in utero were eightfold more likely to be born at a premature gestational age, had significantly lower birthweight and were smaller in length and head circumference than non-exposed infants. There was no association between birth outcomes and maternal depression. At 1 month, the difference in weight in the exposed group became significantly greater than the control group. Antidepressant exposure in utero may affect gestational age at birth and neonatal outcomes independently of antenatal maternal depression. Further studies are needed to examine whether these findings vary according to the type of antidepressant prescribed and follow up growth and development in exposed infants beyond 1 month.


Neosartorya hiratsukae peritonitis through continuous ambulatory peritoneal dialysis.
Fungal peritonitis is a rare, potentially lethal, complication of continuous ambulatory peritoneal dialysis (CAPD). We report what we believe to be the first confirmed Neosartorya hiratsukae CAPD-related peritonitis case in Europe. The patient died, despite early removal of the peritoneal catheter and antifungal therapy. This report highlights the impact of emerging fungal pathogens and the importance of early diagnosis on the outcome in CAPD-related fungal peritonitis.


Experimental analysis of human cigarette smoking behavior.
A laboratory preparation has been developed that permits relatively unobtrusive measurement of naturalistic cigarette smoking behavior in humans. A series of studies is described in which volunteer subjects participated in daily sessions lasting up to 3 h. The first study showed that the intervals between consecutive cigarettes were relatively stable, both within and across sessions. An analysis of puffing for a single cigarette revealed that as the cigarette was smoked, interpuff intervals tended to become longer while puff durations became progressively shorter. The second study showed that cigarette deprivation increased the tendency for subsequent smoking as reflected in latency to smoke and number of cigarettes and puffs. In the third study no change in smoking behavior was detected when subjects were informed that they would subsequently be exposed to a period of cigarette deprivation. The final study demonstrated the responsiveness of cigarette smoking to a form of dose manipulation: decreasing the concentration of tobacco smoke delivered by using ventilated cigarette holders produced increases in the rate of puffing and total numbers of puffs. These studies demonstrate the sensitivity of this preparations and suggest that is may be valuable for exploring a range of pharmacological and behavioral variables that control human cigarette smoking.


Insulin receptor substrate 2 is a negative regulator of memory formation.
Insulin has been shown to impact on learning and memory in both humans and animals, but the downstream signaling mechanisms involved are poorly characterized. Insulin receptor substrate-2 (Irs2) is an adaptor protein that couples activation of insulin- and insulin-like growth factor-1 receptors to downstream signaling pathways. Here, we have deleted Irs2, either in the whole brain or selectively in the forebrain, using the nestin Cre- or D6 Cre-deleter mouse lines, respectively. We show that brain- and forebrain-specific Irs2 knockout mice have enhanced hippocampal spatial reference memory. Furthermore, NesCreIrs2KO mice have enhanced spatial working memory and contextual- and cued-fear memory. Deletion of Irs2 in the brain also increases PSD-95 expression and the density of dendritic spines in hippocampal area CA1, possibly reflecting an increase in the number of excitatory synapses per neuron in the hippocampus that can become activated during memory formation. This increase in activated excitatory synapses might underlie the improved hippocampal memory formation observed in NesCreIrs2KO mice. Overall, these results suggest that Irs2 acts as a negative regulator on memory formation by restricting dendritic spine generation.


Cadmium--copper antagonism in seaweeds inhabiting coastal areas affected by copper mine waste disposals.
Cadmium and copper accumulation by macroalgae was studied in a coastal area exposed to upwelling events and high levels of Cu, the latter resulting from mine disposals. Eight species were studied, and all had very high concentrations of Cd outside of the Cu-contaminated area. Cu in algal tissues was much higher in contaminated than in reference sites. High Cu appeared to suppress Cd bioaccumulation; Cd in algal tissues was much lower in the Cu-contaminated area than in the reference sites. Transplant experiments with Lessonia nigrescens revealed a depuration of Cd in individuals transplanted to areas with high Cu. However, Cd depuration occurs more slowly than Cu uptake. These differences suggest that while Cd and Cu are linked mechanistically, itis nota simple substitution. Overall, the work confirms that macroalgae are useful indicators of metal contamination and may be used as in situ biomonitors for labile forms of metals, like free Cu2+. However, antagonistic relationships between metals must be clearly understood in order to properly interpret their concentrations in macroalgae.


Endothelial nitric oxide synthase and angiotensinogen gene polymorphism in coronary artery diseases in Egypt.
Genetic factors contribute to the pathogenesis of coronary artery disease (CAD). We studied 100 patients with CAD and 50 healthy individuals to assess the association of endothelial nitric oxide (eNOS) polymorphism (Glu298Asp) and angiotensinogen polymorphisms (M235T) and CAD in an Egyptian population. Serum nitric oxide (NO) and angiotensin I levels were also measured. The frequency of Glu298Asp and M235T polymorphisms were higher in the CAD group compared with controls. The mean level of NO was significantly lower (P < .05) while angiotensin I was significantly higher (P < .05) in patients CAD than in controls. The frequency of eNOS TT allele of M235T variant was significantly higher in patients with CAD (20% vs 6%). The frequency of angiotensinogen (AGT) TT and T allele in patients with CAD was significantly higher (P < .05) than in controls (22% vs 6%and 47% vs23%, respectively). Homozygosity for Glu298Asp and M235T polymorphisms may predispose to CAD.


The effect of fibrinoid necrosis on the clinical features and outcomes of primary IgA nephropathy.
To explore the clinicopathologic features and outcomes of IgAN patients who presented with fibrinoid necrosis (FN) lesions or not and the effect of immunosuppressive (IS) treatment in IgAN patients with FN lesions as well. This was a retrospective cohort study with 665 patients diagnosed with primary IgAN from January 2010 to December 2020 in Tianjin Medical University General Hospital and having detailed baseline and follow-up characteristics. Patients were divided into two groups depending on the appearance of FN lesions. Patients with FN lesions were recruited into Group FN1, while patients who were not found FN lesions in their renal biopsy specimens were recruited into Group FN0. Compare the differences between Group FN0 and Group FN1 in baseline clinicopathologic features, treatment solutions and follow-up data as well. To evaluate the impact of different fractions of FN lesions on baseline characteristics and prognosis of IgAN, we subdivided patients in Group FN1 into 3 groups depending on the FN lesions distribution, Mild Group: 0 < FN% < 1/16; Moderate Group: 1/16 < FN% < 1/10; Severe Group: FN% > 1/10. Furthermore, we compared the differences in baseline clinicopathologic features, treatment solutions and follow-up data among these three groups. Kidney endpoint event was defined as patients went into end-stage kidney disease (ESKD), which estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 m^2, regularly chronic dialysis over 6 months or received renal transplantation surgery. The kidney composite endpoint was defined by a ≥ 30% reduction in eGFR, double Scr increase than on-set, ESKD, chronic dialysis over 6 months or renal transplantation. Compare the survival from a composite endpoint rate in different groups by Kaplan-Meier survival curve. The univariate and multivariate Cox models were used to establish the basic model for renal outcomes in patients with FN lesions. (1) A total of 230 patients (34.59%) were found FN lesions in all participants. Patients with FN lesions suffered more severe hematuria than those without. On the hand of pathological characteristic, patients with FN lesions showed higher proportions of M1, E1, C1/C2 and T1/T2 lesions compared with those without FN lesions. (2) The 1-year, 3-year, and 5-year survival of the composite endpoint were lower in the FN1 group than FN0 group. (3) After adjusting for clinicopathological variables, the presence of FN lesions was a significantly independent risk factor for composite endpoint. By using multivariate Cox regression analyses, we also found when the fraction of FN lesions exceeded 10%, the risk of progression into composite endpoint increased 3.927 times. Fibrinoid necrosis of capillary loops is an independent risk factor of poor renal outcomes. More effective treatment should be considered for those who had FN lesions.


Some factors determining differences in the antigenicity of vaccinia virus strains.
The causes determining differences in the antigenicity of different strains of vaccinia virus were investigated in rabbits. A relationship between the antigenicity of a strain and its capacity to multiply in immunized animals was established. Inactivated preparations of the viruses under investigation were capable of stimulating the production of virus neutralizing antibody in vaccinated rabbits. The virus showed the greatest accumulation and the longest persistence in animals vaccinated with the white clone Tashkent strain; similar results were obtained with the B-51 and Lister Institute strains. Strain EM-63 showed the smallest capacity to multiply.


Soleus fiber force and maximal shortening velocity after non-weight bearing with intermittent activity.
This study examined the effectiveness of intermittent weight bearing (IWB) as a countermeasure to non-weight-bearing (NWB)-induced alterations in soleus type I fiber force (in mN), tension (Po; force per fiber cross-sectional area in kN/m-2), and maximal unloaded shortening velocity (Vo, in fiber lengths/s). Adult rats were assigned to one of the following groups: normal weight bearing (WB), 14 days of hindlimb NWB (NWB group), and 14 days of hindlimb NWB with IWB treatments (IWB group). The IWB treatment consisted of four 10-min periods of standing WB each day. Single, chemically permeabilized soleus fiber segments were mounted between a force transducer and position motor and were studied at maximal Ca2+ activation, after which type I fiber myosin heavy-chain composition was confirmed by sodium dodecyl sufate-polyacrylamide gel electrophoresis. NWB resulted in a loss in relative soleus mass (-45%), with type I fibers displaying reductions in diameter (-28%) and peak isometric force (-55%) and an increase in Vo (+33%). In addition, NWB induced a 16% reduction in type I fiber Po, a 41% reduction in type I fiber peak elastic modulus [Eo, defined as (delta force/delta length) x (fiber length/fiber cross-sectional area] and a significant increase in the Po/Eo ratio. In contrast to NWB, IWB reduced the loss of relative soleus mass (by 22%) and attenuated alterations in type I fiber diameter (by 36%), peak force (by 29%), and Vo (by 48%) but had no significant effect on Po, Eo, or Po/Eo. These results indicate that a modest restoration of WB activity during 14 days of NWB is sufficient to attenuate type I fiber atrophy and to partially restore type I peak isometric force and Vo to WB levels. However, the NWB-induced reductions in Po and Eo, which we hypothesize to be due to a decline in the number and stiffness of cross bridges, respectively, are considerably less responsive to this countermeasure treatment.


Fast-Acting Small Molecules Targeting Malarial Aspartyl Proteases, Plasmepsins, Inhibit Malaria Infection at Multiple Life Stages.
The eradication of malaria remains challenging due to the complex life cycle of Plasmodium and the rapid emergence of drug-resistant forms of Plasmodium falciparum and Plasmodium vivax. New, effective, and inexpensive antimalarials against multiple life stages of the parasite are urgently needed to combat the spread of malaria. Here, we synthesized a set of novel hydroxyethylamines and investigated their activities in vitro and in vivo. All of the compounds tested had an inhibitory effect on the blood stage of P. falciparum at submicromolar concentrations, with the best showing 50% inhibitory concentrations (IC50) of around 500 nM against drug-resistant P. falciparum parasites. These compounds showed inhibitory actions against plasmepsins, a family of malarial aspartyl proteases, and exhibited a marked killing effect on blood stage Plasmodium. In chloroquine-resistant Plasmodium berghei and P. berghei ANKA infected mouse models, treating mice with both compounds led to a significant decrease in blood parasite load. Importantly, two of the compounds displayed an inhibitory effect on the gametocyte stages (III-V) of P. falciparum in culture and the liver-stage infection of P. berghei both in in vitro and in vivo. Altogether, our findings suggest that fast-acting hydroxyethylamine-phthalimide analogs targeting multiple life stages of the parasite could be a valuable chemical lead for the development of novel antimalarial drugs.


A population-based prospective study of optic neuritis.
Optic neuritis (ON) is often associated with multiple sclerosis (MS). Early diagnosis is critical to optimal patient management. To estimate the incidence of acute ON and the rates of conversion to MS and antibody-mediated ON. Population-based prospective study was performed in patients with ON from three ophthalmological departments and 44 practicing ophthalmologists from 2014 to 2016. Ophthalmological and neurological examination, magnetic resonance imaging (MRI), determination of aquaporin-4(AQP4)-IgG and myelin-oligodendrocyte glycoprotein (MOG)-IgG were investigated blindly. In all, 63 patients were evaluated and 51 fulfilled the criteria for ON. All were Caucasian, with female:male ratio of 2.2:1 and a median age of 38 years (16-66); 44 (86%) had a single episode of ON (four bilateral), while 7/51 (14%) had recurrent ON. The overall age-specific incidence was 3.28 (2.44-4.31) per 100,000 person years, 2.02 for men and 4.57 for women. At follow-up, 20 patients met the diagnostic criteria for MS, MRI lesions disseminated in space and time in 17/20 patients. AQP4-IgG was detected in none, MOG-IgG was detected in two patients. The prospective incidence of ON was estimated. MRI enabled a diagnosis of MS in a subgroup of patients. Antibody-mediated ON with specificity for MOG was detected in 4% of cases.


Functional-lesion investigation of developmental stuttering with positron emission tomography.
Positron emission tomographic (PET) H2(15)O measurements of resting-state regional cerebral blood flow (CBF) were obtained in 29 right-handed men, 10 of whom stuttered and 19 of whom did not. PET images were analyzed by sampling 74 regions of interest (ROIs), 37 per hemisphere. ROI placement was guided both physiologically and anatomically. Physiological ROI placement was based on speech motor activations. Anatomical ROIs were positioned by reference to a stereotactic, neurosurgical atlas with positions confirmed and finely adjusted by co-registered magnetic-resonance images (MRIs). For all subjects, PET and MR images were normal to visual inspection. Highly significant (p < 0.0001) between-region and between-hemisphere effects were found for both groups, as have been previously reported for normal subjects, but no significant between-group differences were found for any regional CBF values. Analysis by a laterality index found a weakly significant between-groups effect (p = 0.04) that was isolated to five regions, four of which are implicated in speech or hearing. However, these regional laterality effects showed no consistent directionality, nor did these regions have absolute differences in regional blood flow between groups. Present findings do not support recent suggestions that developmental stuttering is associated with abnormalities of brain blood flow at rest. Rather, our findings indicate an essentially normal functional brain terrain with a small number of minor differences in hemispheric symmetry.


Pre-mounted dry TAVI valve with improved endothelialization potential using REDV-loaded PEGMA hydrogel hybrid pericardium.
The pre-mounted dry transcatheter aortic valve implantation (TAVI) valve is a new technology in the development of biological heart valves. Dry valves do not need to be placed in special preservation solution and can be opened and used immediately, meeting the needs of clinical emergency valve implantation. However, current biological valves obtained by simple air drying cannot be unfolded quickly. In addition, the crimping process leads to structural damage to the valve fiber microstructure, reducing the service life of biological valves. Furthermore, current biological valves still have problems such as calcification, endothelialization difficulty, and immune rejection. In this study, a poly(ethylene glycol)methacrylate (PEGMA) hydrogel hybrid pericardium loaded with REDV was developed. The PEGMA monomer solution can penetrate the space of the pericardium. REDV was loaded into the PEGMA hydrogel, which was hybridized with pericardium via in situ polymerization. The results showed improved unfolding properties, less mechanical damage after crimping, and improved endothelialization potential of the biological valve. Thus, REDV-loaded PEGMA hydrogel hybrid pericardium is a promising approach for obtaining pre-mounted dry TAVI valves with enhanced endothelialization properties.


Neurogenic benign fasciculations, pseudomyotonia, and pseudotetany. A disease in search of a name.
We studied two patients with abnormal spontaneous muscular activity. The first had widespread fasciculations, painful spasms, delayed muscular relaxation, and hyperhidrosis. Improvement occurred after several years. The second case had generalized paresthesia, mild stiffness, a positive result from Trusseau's test, and was relieved by administration of carbamazepine. Both patients had abnormal conduction velocity. Examination of muscle biopsy specimens disclosed fiber type grouping and increased collateral ramification of motor axons. These observations exemplify symptoms and signs that resemble those of myotonia and tetany and occasionally occur in partial denervation. they provide additional evidence of the neurogenic nature of Isaacs-Mertens syndrome.


Facial gender interferes with decisions about facial expressions of anger and happiness.
The confounded signal hypothesis maintains that facial expressions of anger and happiness, in order to more efficiently communicate threat or nurturance, evolved forms that take advantage of older gender recognition systems, which were already attuned to similar affordances. Two unexplored consequences of this hypothesis are (1) facial gender should automatically interfere with discriminations of anger and happiness, and (2) controlled attentional processes (like working memory) may be able to override the interference of these particular expressions on gender discrimination. These issues were explored by administering a Garner interference task along with a working memory task as an index of controlled attention. Results show that those with good attentional control were able to eliminate interference of expression on gender decisions but not the interference of gender on expression decisions. Trials in which the stimulus attributes were systematically correlated also revealed strategic facilitation for participants high in attentional control. (PsycINFO Database Record