Endobronchial coils for severe emphysema are effective up to 12 months following treatment: medium term and cross-over results from a randomised controlled trial.
There is a clinical need for therapeutic options to reduce hyperinflation associated with severe emphysema. Endobronchial Coils (coils) are nitinol devices implanted bronchoscopically under fluoroscopic guidance to re-tension the lung. We report the medium term effectiveness and safety of coils in a study of patients with emphysema. Forty five subjects with severe airflow obstruction and hyperinflation received bilateral sequential treatment with coils (30 day interval between treatments) as part of a randomised controlled trial with a primary endpoint 90 days after the final treatment (Clinicaltrials.gov NCT01334307). Further assessments were made at 180 and 360 days and in this study the primary outcome was the effect of coil treatment on the St. George's Respiratory Questionnaire (SGRQ) 360 days following treatment. At 360 days following treatment, there was an improvement in the SGRQ score of -6.1±14.0 points (p = 0.01) compared to baseline. Improvements in secondary outcomes were seen with increases in forced expiratory volume in the first second of 8.9 ±22.2% (p = 0.002) and 6-minute walking distance of 34.1±52.4m (p = 0.003). The safety profile was acceptable out to 360 days post-treatment. Statistically and clinically meaningful benefits in quality of life, exercise capacity and pulmonary function in patients treated with coils are sustained twelve months after treatment. Clinicaltrials.gov NCT01334307.


Is Ultrasonography a Useful Method to Evaluate the Effectiveness of Complex Decongestive Therapy in Breast Cancer-related Lymphedema?
In recent years the use of ultrasonography has become widespread in the field of lymphedema especially as an aid for diagnosis. The aim of this study was to evaluate whether ultrasonography is a useful method to assess the efficacy of complex decongestive therapy (CDT). Circumferences and ultrasonographic evaluations (cutis and subcutis thickness) were performed at 10 cm proximal and distal to the elbow and limb volume (upper and forearm) was calculated from circumferences at six anatomic landmarks by using truncated cone formula. Measurements were recorded before and after CDT on both sides. A total of twenty-six women (mean age 51.3 ± 10.8) with the diagnosis of breast cancer-related lymphedema (BCRL) were enrolled in the study. Significant reduction in the subcutis thickness was observed on the affected side after the treatment period, and the percentage change in subcutis thickness was correlated with the percentage change in edema. This study also demonstrated that the soft tissue thickness was higher in the affected arm and ultrasonographic findings were consistent with the other measurement methods (circumferences and limb volumes). Considering that ultrasound imaging is patient-friendly, non-invasive, and cost-effective, we recommend its more widespread use for evaluating treatment efficacy in BCRL.


Oxidative Stress and Nitric Oxide in Autism Spectrum Disorder and Other Neuropsychiatric Disorders.
The etiology of autism spectrum disorder (ASD) remains unclear; however, the toxic environmental exposure to oxidative stress has been suggested to play an important role in its pathogenesis. A loss of balance between oxidative stress and antioxidant capacity produces an excess of reactive nitrogen species (RNS) such as nitric oxide (NO). Polyunsaturated fatty acids (PUFAs), particularly arachidonic acid, docosahexaenoic acid and eicosapentaenoic acid, are closely related to NO and NO synthase. In the pathophysiology of ASD, NO is related to the activity of primary PUFAs. NO modulates short- and long-term synaptic plasticity and plays essential roles in the regulation of a wide range of physiological processes including neurotransmission. NO affects the function of reactive oxygen species (ROS) in the local cellular milieu, in which biological antioxidants are present. NO plays a double role in the organism showing both neuroprotective and neurotoxic effects. Redox imbalance leads to the activation of the neurotoxic pathway, suggesting crossroads for the neurotoxic or neuroprotective effects of NO. Furthermore, the dual role of NO could depend on the adaptive functions of the antioxidant capacity and oxidative stress-related ROS/RNS as the disease progresses. Increased concentrations of arachidonic acid promote neuronal survival, and the dysregulation of the NO system plays an important role in the pathophysiology of bipolar disorder and recurrent depressive disorders. Therefore, the NO system could provide useful drug targets for these diseases. NO and NO donors also show therapeutic potential for Alzheimer's disease and schizophrenia with refractory symptoms and cognitive dysfunction.


Mental health care in the accountable care organization.
The Centers for Medicare and Medicaid Services (CMS) is promoting formation of accountable care organizations (ACOs). In these population-based models, CMS aligns a Medicare beneficiary population to an ACO with associated expenditure and quality targets, transitioning away from purely volume-based revenue of fee-for-service Medicare. Patients with mental illness are among high-cost Medicare beneficiaries, but this population has received little attention in ACO implementation. Although the ACO goals of providing chronic and preventive care in a coordinated, patient-centered manner are consistent with what some mental health providers have long advocated, the population-based orientation may be unfamiliar. In addressing the needs of high-cost, high-risk patients to meet quality and expenditure targets, an ACO should examine the quality of mental health care it provides as well as medical quality for patients with mental illness. In addition, federal agencies should invest to ensure understanding of the impact of population-based initiatives on patients with mental illness.


Loss of Cln5 causes altered neurogenesis in a mouse model of a childhood neurodegenerative disorder.
Neural stem/progenitor cells (NPCs) generate new neurons in the brain throughout an individual's lifetime in an intricate process called neurogenesis. Neurogenic alterations are a common feature of several adult-onset neurodegenerative diseases. The neuronal ceroid lipofuscinoses (NCLs) are the most common group of inherited neurodegenerative diseases that mainly affect children. Pathological features of the NCLs include accumulation of lysosomal storage material, neuroinflammation and neuronal degeneration, yet the exact cause of this group of diseases remains poorly understood. The function of the CLN5 protein, causative of the CLN5 disease form of NCL, is unknown. In the present study, we sought to examine neurogenesis in the neurodegenerative disorder caused by loss of Cln5 Our findings demonstrate a newly identified crucial role for CLN5 in neurogenesis. We report for the first time that neurogenesis is increased in Cln5-deficient mice, which model the childhood neurodegenerative disorder caused by loss of Cln5 Our results demonstrate that, in Cln5 deficiency, proliferation of NPCs is increased, NPC migration is reduced and NPC differentiation towards the neuronal lineage is increased concomitantly with functional alterations in the NPCs. Moreover, the observed impairment in neurogenesis is correlated with increased expression of the pro-inflammatory cytokine IL-1β. A full understanding of the pathological mechanisms that lead to disease and the function of the NCL proteins are critical for designing effective therapeutic approaches for this devastating neurodegenerative disorder.


Comparing the hta core model with a national health technology assessment report.
The HTA Core Model is a framework for producing health technology assessments (HTAs) in a structured format. The Model splits the content of a HTA into assessment elements. The objective is to explore the adaptability of these assessment elements in national report production in a pilot case study comparing a national HTA report and the HTA Core Model. An on-going Dutch HTA report on endovascular repair of abdominal aortic aneurysm (EVAR) was chosen as a typical representative of a national report on medical interventions. The author of the EVAR report assessed the relevance and comprehensiveness of the assessment elements of the HTA Core Model for her work. Another researcher annotated the Core Model specific content in the EVAR report. Matching and missing content, as well as the distribution of information in the EVAR report were tabulated and analysed in joint deliberations. Forty percent of the assessment elements of the Core Model were considered relevant for the EVAR report. Some issues relevant for EVAR but missing from the Core Model were identified: they were about re-interventions, secondary prevention, subpopulations that benefit most, and the length of the hospital stay. The distribution of information differed substantially between the Code Model and the national report. The assessment elements of the HTA Core Model covered most relevant questions of the national report. In order to facilitate easy adaptation of information, the distribution of information should be more consistent in the national report and the Core model.


Fast and Sensitive Bioanalytical Method for the Determination of Deucravacitinib in Human Plasma Using HPLC-MS/MS: Application and Greenness Evaluation.
Plaque psoriasis is a common, long-lasting illness that affects the immune system and causes significant negative impacts on a patient's physical health, well-being, and ability to work effectively. Deucravacitinib (DEU) is the first oral medication used in the treatment of plaque psoriasis, a chronic skin condition that causes red, scaly patches on the skin. DEU is a type of medication called an oral Janus kinase (JAK) inhibitor, which works by blocking specific enzymes that play a role in the inflammation and immune response associated with psoriasis. Therefore, a quick, easy, novel, reliable, sensitive, and straightforward liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach was used to analyze DEU in plasma samples. The LC-MS/MS method for the determination of DEU in human plasma was based on using trimethoprim as an internal standard (IS). The separation of DEU and IS was carried out via liquid-liquid extraction (LLE). The extract was then subjected to the chromatographic system separation using the ACE-C18 column (4.6 × 100 mm, 5 µm). The mobile phase employed consisted of methanol and a solution of 2 mM ammonium formate (80:20 v/v, respectively). The flow rate used was set at 0.9 mL min-1. The creative strategy was performed by running an ABSCIEX API 4000 mass spectrometer with an electron spray ionization source in multiple reaction monitoring (MRM) mode. The ion transitions m/z 426.3 → 358.2 were used for DEU quantitation, while the ion transitions m/z 291.1 → 261.1 were used for trimethoprim quantitation. The accuracy, precision, linearity, recovery, and selectivity of DEU were deemed acceptable when validated for a concentration range between 0.500 and 601.050 ng/mL, utilizing a weighting factor of 1/x2.


Ectromelia, vaccinia and cowpox viruses encode secreted interleukin-18-binding proteins.
Interleukin-18 (IL-18) is a proinflammatory cytokine that plays a key role in the activation of natural killer and T helper 1 cell responses principally by inducing interferon-gamma (IFN-gamma). Human and mouse secreted IL-18-binding proteins (IL-18BPs) have recently been described which block IL-18 activity but have no sequence similarity to membrane IL-18 receptors. Several poxvirus genes encode proteins with sequence similarity to IL-18BPs. Here we show that vaccinia, ectromelia and cowpox viruses secrete from infected cells a soluble IL-18BP (vIL-18BP) that may modulate the host antiviral response. The ectromelia virus protein was found to block NF-kappaB activation and induction of IFN-gamma in response to IL-18. The highly attenuated vaccinia virus modified virus Ankara encodes IL-18-binding activity, and thus deletion of the vIL-18BP may improve further the safety and immunogenicity of this promising human vaccine candidate. We confirm that molluscum contagiosum virus, a molluscipoxvirus that produces small skin tumours in immunocompetent individuals and opportunistic infections in immunodeficient AIDS patients, also encodes a related, larger vIL-18BP (gene MC54L). This protein may contribute to the lack of inflammatory response characteristic of molluscum contagiosum virus lesions. The expression of vIL-18BPs by distinct poxvirus genera that cause local or general viral dissemination, or persistent or acute infections in the host, emphasizes the importance of IL-18 in response to viral infections.


PATHOGENESIS OF INFLAMMATION. I. THE PRODUCTION OF AN INFLAMMATORY SUBSTANCE FROM RABBIT GRANULOCYTES IN VITRO AND ITS RELATIONSHIP TO LEUCOCYTE PYROGEN.
Material obtained from the in vitro incubation of granulocytes from saline-induced peritoneal exudates of rabbits has been shown to produce inflammation and fever in rabbits. The supernatant material from cells incubated in saline has been termed granulocytic substance (GS) and is heat-labile. Its production is temperature dependent, occurring at 37 degrees C but not at 4 degrees C, requires viable cells, and is inhibited by potassium ions. A similar material is liberated when cells are incubated in a more physiologic medium. Freezing and thawing of granulocytes does not release GS and the active principle cannot be obtained from the incubation of lymphocytes. GS produces a delayed inflammatory response as measured by leucocyte sticking and emigration in the rabbit ear chamber and the leakage of protein-conjugated dye at the site of intradermal injection. The former response can be accurately quantitated by calculation of the inflammatory index from reactions observed in the ear chamber. The inflammatory reaction and the properties of GS distinguish it from a variety of previously described mediators of inflammation, but GS appears to be identical with leucocytic pyrogen. The possible role of GS in delayed and protracted inflammation and its relationship to the pathogenesis of fever are discussed.


Implementation of treatment guidelines for specialist mental health care.
A huge gap exists between the production of evidence and its take-up in clinical practice settings. To fill this gap, treatment guidelines, based on explicit assessments of the evidence base, are commonly employed in several fields of medicine, including schizophrenia and related psychotic disorders. It remains unclear, however, whether treatment guidelines have any impact on provider performance and patient outcomes, and how implementation should be conducted to maximise benefit. The primary objective of this review was to examine the efficacy of guideline implementation strategies in improving process outcomes (performance of healthcare providers) and patient outcomes. We additionally explored which components of different guideline implementation strategies can influence process and patient outcomes. We searched the Cochrane Schizophrenia Group Register (March 2012), as well as references of included studies. Studies that examined schizophrenia-spectrum disorders to compare guideline implementation strategies with usual care or to assess the comparative efficacy of different guideline implementation strategies. Review authors worked independently and in duplicate to critically appraise records from 882 studies; five individual studies met the inclusion criteria and were considered. As critical appraisal of the five included studies revealed substantial heterogeneity in terms of focus of the guideline, target of the intervention, implementation strategy and outcome measures, meta-analysis was carried out for antipsychotic co-prescribing only. Of the five included studies, practitioner impact was assessed in three. The five studies were generally at unclear risk of bias, and all evidence in the 'Summary of findings' table was graded by review authors as of very low quality. Meta-analysis of two studies revealed that a combination of several guideline dissemination and implementation strategies targeting healthcare professionals did not reduce antipsychotic co-prescribing in schizophrenia outpatients (two studies, n = 1,082, risk ratio (RR) 1.10, 95% confidence interval (CI) 0.99 to 1.23; corrected for cluster design: n = 310, RR 0.97, CI 0.75 to 1.25). One trial, which studied a nurse-led intervention aimed at promoting cardiovascular disease screening, found a significant effect in terms of the proportion of people receiving screening (blood pressure: n = 96, RR 0.07, 95% CI 0.02 to 0.28; cholesterol: n = 103, RR 0.46, 95% CI 0.30 to 0.70; glucose: n = 103, RR 0.53, 95% CI 0.34 to 0.82; BMI: n = 99, RR 0.22, 95% CI 0.08 to 0.60; smoking status: n = 96, RR 0.28, 95% CI 0.12 to 0.64; Framingham score: n = 110, RR 0.69, 95% CI 0.55 to 0.87), although in the analysis corrected for cluster design, the effect was statistically significant for blood pressure and cholesterol only (blood pressure, corrected for cluster design: n = 33, RR 0.10, 95% CI 0.01 to 0.74; cholesterol, corrected for cluster design: n = 35, RR 0.49, 95% CI 0.24 to 0.99; glucose, corrected for cluster design: n = 35, RR 0.58, 95% CI 0.28 to 1.21; BMI, corrected for cluster design: n = 34, RR 0.18, 95% CI 0.02 to 1.37; smoking status, corrected for cluster design: n = 32, RR 0.25, 95% CI 0.06 to 1.03; Framingham score, corrected for cluster design: n = 38, RR 0.71, 95% CI 0.48 to 1.03; very low quality). Regarding participant outcomes, one trial assessed the efficacy of a shared decision-making implementation strategy and found no impact in terms of psychopathology, satisfaction with care and drug attitude. Another single trial studied a multifaceted intervention to promote medication adherence and found no impact in terms of adherence rates. With only five studies meeting inclusion criteria, and with limited low or very low quality usable information, it is not possible to arrive at definitive conclusions. The preliminary pattern of evidence suggests that, although small changes in psychiatric practice have been demonstrated, uncertainty remains in terms of clinically meaningful and sustainable effects of treatment guidelines on patient outcomes and how best to implement such guidelines for maximal benefit.


A novel phenotype associated with the R162W variant in the KCNJ13 gene.
Pathogenic variants in KCNJ13 have been associated with both autosomal dominant Snowflake vitreoretinal degeneration (SVD) and autosomal recessive Leber congenital amaurosis. SVD is characterized by aberrant vitreoretinal interface leading to increased risk of retinal detachment, crystalline retinal snowflake deposits, optic disc abnormalities, early-onset cataract, and cornea guttae. Reduced dark adaptation and reduced scotopic rod b-waves have also been described. We report a novel phenotype associated with the R162W variant in KCNJ13. Four affected members of a Swedish family were included. Three of them were examined with best corrected visual acuity, Goldmann perimetry, full-field-and multifocal electroretinography, optical coherence tomography, fundus color photographs, fundus autofluorescence images, slit lamp inspection, and genetic testing. The fourth subject only managed genetic testing. All subjects carry the pathogenic missense variant; c.484C>T (NM_002242.4), R162W, in KCNJ13. ERG measurements revealed reduced macular-as well as general retinal function. Two of the subjects had a history of retinal detachment and the two younger subjects demonstrated early onset cataract. They all had structural macular changes and slightly gliotic optic discs. In this family, the R162W variant in KCNJ13, previously described in association with SVD, causes a somewhat novel phenotype including macular dystrophy and moderate reduction of general retinal function as the main features combined with disc abnormalities, retinal detachment, and presenile cataract that has been described before. In times of up-coming gene-based therapies, it is important to report new genotype-phenotype associations to improve the possibilities to identify future treatment candidates.


Rigidochromism by imide functionalisation of an aminomaleimide fluorophore.
Fluorescent dyes that exhibit high solid state quantum yields and sensitivity to the mechanical properties of their local environment are useful for a wide variety of applications, but are limited in chemical diversity. We report a trityl-functionalised maleimide that displays rigidochromic behaviour, becoming highly fluorescent when immobilised in a solid matrix, while displaying negligible fluorescence in solution. Furthermore, the dye's quantum yield is shown to be sensitive to the nature of the surrounding matrix. Computational studies reveal that this behaviour arises from the precise tuning of inter- and intramolecular noncovalent interactions. This work expands the diversity of molecules exhibiting solid state environment sensitivity, and provides important fundamental insights into their design.


Prolactin binding to mammary gland, 7,12-dimethylbenz(a)-anthracene-induced mammary tumors, and liver in rats.
Specific binding of radioactively labeled prolactin was determined in membrane preparations from mammary glands and livers of rats during pregnancy and lactation. Prolactin binding to mammary gland increased throughout late pregnancy and early lactation, reached a maximum on Day 11 of lactation, and then declined. Maximum prolactin binding to liver membrane preparations was observed during late pregnancy and declined throughout lactation. Estradiol benzoate (20 mug/day), administered on Days 5 to 10 of lactation, reduced prolactin binding to mammary gland by 55%, increased binding to liver 2-fold, and reduced litter weight gain by 25%. Prolactin binding to 7,12-dimethylbenz(a)anthracene-induced mammary tumors was 3 times higher than that observed in lactating mammary gland. Administration of prolactin enhanced tumor growth but decreased specific prolactin binding to tumors. Lergotrile mesylate inhibited and estradiol benzoate (2 mug/day) enhanced tumor growth, but neither treatment affected prolactin binding to tumor membrane preparations. In contrast, higher doses of estradiol benzoate (20 mug/day) inhibited tumor growth and reduced prolactin binding. Prolactin binding varied widely within all groups of mammary tumors and was not clearly related to growth response or to altered circulating estrogen and/or prolactin levels. Hormone dependence in this animal tumor model is complex and may not be predicted on the basis of prolactin-binding capacity alone.


Direct intracerebral nerve growth factor gene transfer using a recombinant adenovirus: effect on basal forebrain cholinergic neurons during aging.
Gene therapy in the nervous system offers an attractive strategy for the administration of therapeutic factors in a potentially region-specific, sustained, and well-tolerated manner. We tested the trophic effect of a recombinant adenovirus encoding nerve growth factor (AdNGF) in vivo on basal forebrain cholinergic neurons of aged rats, a neuronal population affected during normal and pathological aging. Three weeks after unilateral injection of the recombinant adenovirus into the nucleus basalis magnocellularis, a significant increase in the somal areas of cholinergic neurons ipsilateral to the injection was observed. No increase was detected in animals receiving a recombinant adenovirus carrying the Escherichia coli Lac Z reporter gene. Injected animals did not lose weight, an adverse effect usually described after intracerebroventricular infusion of NGF, and no tissue loss or massive local inflammatory response was observed around injection sites. Thus, a single intracerebral injection of AdNGF produces trophic effects similar to those resulting from chronic intracerebroventricular high levels of NGF. These findings indicate that recombinant adenoviruses encoding growth factors are potentially powerful tools for improving neuronal deficits associated with degenerative processes.


Cyanobacterial cyclopeptides as lead compounds to novel targeted cancer drugs.
Cyanobacterial cyclopeptides, including microcystins and nodularins, are considered a health hazard to humans due to the possible toxic effects of high consumption. From a pharmacological standpoint, microcystins are stable hydrophilic cyclic heptapeptides with a potential to cause cellular damage following uptake via organic anion-transporting polypeptides (OATP). Their intracellular biological effects involve inhibition of catalytic subunits of protein phosphatase 1 (PP1) and PP2, glutathione depletion and generation of reactive oxygen species (ROS). Interestingly, certain OATPs are prominently expressed in cancers as compared to normal tissues, qualifying MC as potential candidates for cancer drug development. In the era of targeted cancer therapy, cyanotoxins comprise a rich source of natural cytotoxic compounds with a potential to target cancers expressing specific uptake transporters. Moreover, their structure offers opportunities for combinatorial engineering to enhance the therapeutic index and resolve organ-specific toxicity issues. In this article, we revisit cyanobacterial cyclopeptides as potential novel targets for anticancer drugs by summarizing existing biomedical evidence, presenting structure-activity data and discussing developmental perspectives.


Expressed protein ligation: a general method for protein engineering.
A protein semisynthesis method-expressed protein ligation-is described that involves the chemoselective addition of a peptide to a recombinant protein. This method was used to ligate a phosphotyrosine peptide to the C terminus of the protein tyrosine kinase C-terminal Src kinase (Csk). By intercepting a thioester generated in the recombinant protein with an N-terminal cysteine containing synthetic peptide, near quantitative chemical ligation of the peptide to the protein was achieved. The semisynthetic tail-phosphorylated Csk showed evidence of an intramolecular phosphotyrosine-Src homology 2 interaction and an unexpected increase in catalytic phosphoryl transfer efficiency toward a physiologically relevant substrate compared with the non-tail-phosphorylated control. This work illustrates that expressed protein ligation is a simple and powerful new method in protein engineering to introduce sequences of unnatural amino acids, posttranslational modifications, and biophysical probes into proteins of any size.


[Potentialities of conservative and surgical treatment of patients with congenital microphthalmia and anophthalmia].
Congenital anophthalmia and microphthalmia were responsible for 1.7-1.8% cases of all cases treated at laboratory of plastic surgery and ocular prostheses. Clinical picture of the condition is described. The philosophy of rehabilitation of patients with congenital anophthalmia and microphthalmia is as follows: 1) no operations during the first years of life; 2) early staged fitting with prostheses; 3) surgical treatment in older age, when the resources of conservative extension of the cavity are exhausted. The authors emphasize that active conservative treatment should be preferred. Method for nonsurgical extension of the conjunctival cavity by staged insertion of prostheses is described. Positive and negative aspects of surgical treatments are discussed. The authors emphasize that surgical activity in early age is extremely harmful. Results of surgical treatment of 27 patients are presented. The patients were divided into 2 groups differing by the tasks of surgery: repair of consequences of previous operations (59.2% cases) and typical correction of the eye lids (40.8%). Clinical examples are offered.


Phosphatidylglycerol and surfactant: A potential treatment for COVID-19?
A hypothesis concerning the potential utility of surfactant supplementation for the treatment of critically ill patients with COVID-19 is proposed, along with a brief summary of the data in the literature supporting this idea. It is thought that surfactant, which is already approved by the Food and Drug Administration for intratracheal administration to treat neonatal respiratory distress syndrome in pre-term infants, could benefit COVID-19-infected individuals by: (1) restoring surfactant damaged by lung infection and/or decreased due to the virus-induced death of the type II pneumocytes that produce it and (2) reducing surface tension to decrease the work of breathing and limit pulmonary edema. In addition, a constituent of surfactant, phosphatidylglycerol, could mitigate COVID-19-induced lung pathology by: (3) decreasing excessive innate immune system stimulation via its inhibition of toll-like receptor-2 and -4 activation by microbial components and cellular proteins released by damaged cells, thereby limiting inflammation and the resultant pulmonary edema, and (4) possibly blocking spread of the viral infection to non-infected cells in the lung. Therefore, it is suggested that surfactant preparations containing phosphatidylglycerol be tested for their ability to improve lung function in critically ill patients with COVID-19.


Allelochemicals in foliage of unfavored tree hosts of the gypsy moth,Lymantria dispar L. : 2. Seasonal variation of saponins inilex opaca and identification of saponin aglycones.
A greater variety of qualitative chemical defenses has been reported in eastern forest trees than might be expected from current interpretation of the plant apparency theory. For the gypsy moth there is an association between the occurrence of alkaloids and unfavorability of certain tree species, as well as the presence of saponins. The latter association, however, is not statistically significant. Species in the genusIlex have been reported to contain both alkaloids and saponins (Barbosa and Krischick, 1987). In this study, determinations were made of the occurrence of alkaloids and saponins inI. opaca and their changes in concentration over time. No alkaloids were detected. Saponins were isolated, and the aglycone siaresinolic acid was identified. Saponin concentration changes seasonally, being highest in early May and lowest in early June leaves.


Application of Indirect Immunofluorescence on the Diagnosis of Pemphigus.
Pemphigus is an autoimmune bullous disease, and although several diagnostic methods are now in use indirect immunofluorescence (IIF) is still considered an important tool for diagnosing pemphigus because of its convenience, repeatability, and reduced pain for patients. The goal of the present study was to evaluate the diagnostic value of IIF on normal human skin (NS), monkey esophagus (ME), and salt-split skin (SS) for better diagnosis of pemphigus. Clinical data of 70 patients with pemphigus and 56 control were collected. IIF on NS, ME, and SS were assessed separately by observing fluorescein deposition and comparing its differentiation to different kinds of pemphigus and its sensitivities and specificities to different substrates. Intercellular deposition of IgG was visible when IIF on NS, ME, and SS were positive in patients with pemphigus. Their corresponding sensitivities and specificities were 30.0%, 84.3%, and 70.0% and 96.4%, 96.4%, and 94.6%, respectively. The differences in sensitivity were statistically significant between NS and ME and between NS and SS (P<0.001) and the specificities among the three substrates were not statistically significantly different (P>0.05). As for different types of pemphigus, the sensitivities between NS and ME and between NS and SS were statistically significantly different in both Dsg1- and Dsg3-positive and only Dsg1-positive patients with pemphigus (P<0.01); the sensitivities between NS and ME were statistically significantly different only in Dsg3-positive patients with pemphigus (P<0.001); there were no statistically significant differences between ME and SS. We therefore propose that ME is a good substrate for pemphigus diagnosis with higher sensitivity and superior to NS, particularly for patients with anti-Dsg3 antibodies. SS is a good alternative substrate to ME with almost identical higher sensitivities and specificities for diagnosis of pemphigus.


[Lymphoscintigraphy with double tracer technique in carcinomas of the head-neck region].
Lymphoscintigraphy has been used since the early 1960s to demonstrate lymphatic drainage of head and neck tumors, but did not prove satisfactory. With the increasing importance of highly sophisticated neck dissection procedures, lymphoscintigraphy may have greater diagnostic impact. This assumes that lymphoscintigraphy will allow an accurate correlation of lymphatic drainage with anatomic structures. In this paper, we report on a method of lymphoscintigraphy with simultaneous body contouring. Double-tracer lymphoscintigraphy was performed in 78 patients with squamous cell carcinoma. Patients received 100 MBq 99mTc-colloid in 0.1-0.2 ml in 3-4 peritumoral localizations. Ten patients were injected during surgery. Two milliliters of perchlorate solution were given orally in order to block the thyroid. Twenty minutes later patients received 50 MBq 99mTc-pertechnetate i.v. for body contouring. Planar images were obtained over 5 min each at 30 min and 4-6 h after injection from anterior, right lateral and left lateral using a LFOV-gamma camera. The thyroid was not visualized in any of the patients. In 28 of 78 patients (36%), the injection site was the only focal activity seen. In 50 of 78 patients (64%), lymph drainage was observed. Thirty-six of 78 patients (46%) showed unilateral lymphatic drainage, and 14 of 78 (18%) showed bilateral drainage. In all 50 patients showing lymphatic drainage, lymph nodes could be easily assigned to the six cervical lymph node compartments described. Double-tracer lymphoscintigraphy enables an accurate correlation of cervical lymph nodes and anatomic structures of the head and neck region. These findings suggest that the impact of these studies on the preoperative planning for neck dissection should be reevaluated.


[Tremor of unknown origin. What can the family physician do?].
Tremor is a very frequent neurological symptom with a wide range of causes. For drug- or toxin-induced tremor, the primary disease must be treated and, accordingly, the medication discontinued or the dosage changed. The most common neurological tremors, Parkinson's tremor and essential tremor, can be usually easily differentiated from one another on the basis of their symptoms. If the patient is significantly disabled, the tremors should be treated with drugs in collaboration with a neurologist. For drug therapy resistant, severely disabled patients, a stereotactic surgical treatment could be performed in which the thalamus is stimulated through an implanted brain electrode.


Salmonella enterica serotype Typhimurium MisL is an intestinal colonization factor that binds fibronectin.
MisL is an autotransporter protein encoded by Salmonella pathogenicity island 3 (SPI3). To investigate the role of MisL in Salmonella enterica serotype Typhimurium (S. Typhimurium) pathogenesis, we characterized its function during infection of mice and identified a host receptor for this adhesin. In a mouse model of S. Typhimurium intestinal persistence, a misL mutant was shed with the faeces in significantly lower numbers than the wild type and was impaired in its ability to colonize the cecum. Previous studies have implicated binding of extracellular matrix proteins as a possible mechanism for S. Typhimurium intestinal persistence. A gluthathione-S-transferase (GST) fusion protein to the MisL passenger domain (GST-MisL(29-281)) was constructed to investigate binding to extracellular matrix proteins. In a solid-phase binding assay the purified GST-MisL(29-281) fusion protein bound to fibronectin and collagen IV, but not to collagen I. MisL expression was not detected by Western blot in S. Typhimurium grown under standard laboratory conditions. However, when expression of the cloned misL gene was driven by the Escherichia coli arabinose promoter, MisL could be detected in the S. Typhimurium outer membrane by Western blot and on the bacterial cell surface by flow cytometry. Expression of MisL enabled S. Typhimurium to bind fibronectin to its cell surface, resulting in attachment to fibronectin-coated glass slides and in increased invasiveness for human epithelial cells derived from colonic carcinoma (T84 cells). These data identify MisL as an extracellular matrix adhesin involved in intestinal colonization.


Muscle wasting and interleukin-6-induced atrogin-I expression in the cachectic Apc ( Min/+ ) mouse.
Interleukin-6 (IL-6) is necessary for cachexia in Apc ( Min/+ ) mice, but the mechanisms inducing this myofiber wasting have not been established. The purpose of this study was to examine gastrocnemius muscle wasting in the Apc ( Min/+ ) mouse and to determine IL-6 regulated mechanisms contributing to muscle loss. Gastrocnemius type IIB mean fiber cross-sectional area (CSA) from Apc ( Min/+ ) mice decreased 32% between 13 and 22 weeks of age. Apc ( Min/+ ) mice lacking IL-6 did not have type IIB fiber atrophy, while overexpression of circulating IL-6 exacerbated the loss of type IIB fiber CSA in Apc ( Min/+ ) mice. Muscle Atrogin-I mRNA expression was induced at least ninefold at 18 and 22 weeks of age compared to 13-week-old mice. Atrogin-I gene expression was also induced by overexpression of circulating IL-6. These data suggest that high circulating IL-6 levels induce type IIB fiber CSA loss in Apc ( Min/+ ) mice, and circulating IL-6 is sufficient to regulate Atrogin-I gene expression in cachectic mice.


Perceptions of human attractiveness comprising face and voice cues.
In human mate choice, sexually dimorphic faces and voices comprise hormone-mediated cues that purportedly develop as an indicator of mate quality or the ability to compete with same-sex rivals. If preferences for faces communicate the same biologically relevant information as do voices, then ratings of these cues should correlate. Sixty participants (30 male and 30 female) rated a series of opposite-sex faces, voices, and faces together with voices for attractiveness in a repeated measures computer-based experiment. The effects of face and voice attractiveness on face-voice compound stimuli were analyzed using a multilevel model. Faces contributed proportionally more than voices to ratings of face-voice compound attractiveness. Faces and voices positively and independently contributed to the attractiveness of male compound stimuli although there was no significant correlation between their rated attractiveness. A positive interaction and correlation between attractiveness was shown for faces and voices in relation to the attractiveness of female compound stimuli. Rather than providing a better estimate of a single characteristic, male faces and voices may instead communicate independent information that, in turn, provides a female with a better assessment of overall mate quality. Conversely, female faces and voices together provide males with a more accurate assessment of a single dimension of mate quality.


[Choriocarcinoma of the uterus after term pregnancy: imaging by vaginal color Doppler ultrasound].
A 29 year-old woman presented with continuous metrorrhagia and a positive pregnancy test 3 1/2 months after vaginal birth. Transvaginal sonography showed a 3.5 x 4 x 4 cm mostly echogenic uterine mass with diffuse myometrial invasion in the right fundal region. Colour Doppler sonography revealed extensive low impedance flow in the periphery of the mass suggestive of a trophoblastic tumor. Histological examination of curettage specimens revealed a chorionic carcinoma. The tumor size as measured by magnetic resonance imaging correlated well with that by sonography. Trophoblastic disease after a normal pregnancy is rare. Early diagnosis can be facilitated by transvaginal colour Doppler sonography.


The natural activation ability of subsurface media to promote in-situ chemical oxidation of 1,4-dioxane.
The ability of soils and sediments to promote in-situ activation of persulfate and persulfate combined with hydrogen peroxide was investigated for treatment of 1,4-dioxane (dioxane). Experiments were conducted with both batch-reactor and column systems to examine reaction rates and activation mechanisms. Four soils and aquifer sediments were used. ICP-MS and XRD analyses were used to characterize geochemical properties of the solutions and sediments, while EPR spectroscopy was used to characterize radical formation. For the batch experiments, degradation of dioxane was significantly greater in the presence of each of the four subsurface geomedia compared to the controls with no geomedia. This indicates that all four geomedia induced oxidant activation, thereby enhancing dioxane degradation. Dioxane degradation was significantly enhanced by the addition of peroxide to the persulfate solution. It is hypothesized that iron associated with the geomedia is primarily responsible for activation, and that the degree of degradation enhancement relates in part to dissolved-phase iron content. EPR results indicate that manganese oxides and soil organic matter may also have contributed to some degree to persulfate activation, and that manganese oxides enhanced activation of peroxide under the study conditions. Approximately 10% of dioxane was degraded in the miscible-displacement experiments, consistent with the short residence time compared to dioxane's half-life. The pseudo first-order rate coefficients obtained from the batch and column experiments were similar. The results of this study indicate that subsurface geomedia can induce activation of persulfate and peroxide to enhance in-situ chemical oxidation applications.


Low loss high index contrast nanoimprinted polysiloxane waveguides.
Nanoimprint lithography is gaining rapid acceptance in fields as diverse as microelectronics and microfluidics due to its simplicity high resolution and low cost. These properties are critically important for the fabrication of photonic devices, where cost is often the major inhibiting deployment factor for high volume applications. We report here on the use of nanoimprint technology to fabricate low loss broadband high index contrast waveguides in a Polysiloxane polymer system for the first time.


[Topical organization of the cat inferior colliculus under conditions of the simulated sound source motion].
Binaurally presented click trains with gradually changing ITDs were used to imitate the sound source motion. Focal EP-trains from the cat inferior colliculus, IC, were recorded, and changing amplitude of the successive EPs following successive clicks was taken for estimation of the motion effect (ME). It was shown that a) in 25% of cases the ME depends on the motion direction; b) the ME is better presented ipsilaterally in respect to the recording point, with equal dependence on motion velocity both on the left and on the right; c) the ME phenomenon is connected with prevalence of contralateral afferentation as compared to the ipsilateral one; d) the ME is connected with inhibitory phenomena such as binaural suppression of monaural afferentation; e) the ME of the best amplitude is most pronounced in the ventrolateral area of the IC central nucleus, its localisation being near to that of the great multipolar neurones, whereas slightly and moderately pronounced MEs are presented rather uniformly over the central nucleus like the "basic" neurones are; MEs of different pronouncement are supposed to depend differently on effectiveness of ipsi- and contralateral stimulation--in accordance with properties of multipolar and "basic" neurons.


Central nucleus of amygdala projections to rostral ventrolateral medulla neurones activated by decreased blood pressure.
The central nucleus of amygdala (CeA) participates in cardiovascular regulation during emotional behaviour but it has not been established whether any of these effects are mediated through its direct connections to blood pressure-regulating neurones in the rostral ventrolateral medulla (RVLM). The RVLM contains barosensitive neurones that maintain resting blood pressure via their projections to sympathetic preganglionic neurones in the thoracic spinal cord. In this study on rats, we used combined anterograde neuronal tracing of CeA projections with confocal and electron microscopic immunohistochemical detection of phenylethanolamine-N-methyltransferase, the adrenaline-synthesizing enzyme present in C1 catecholamine neurones of the RVLM, and Fos, the protein product of the c-fos proto-oncogene. Fos expression in barosensitive neurones was stimulated by an intravenous infusion of the hypotensive agent sodium nitroprusside. Injection of the tracer biotin dextran amine (10-kDa form) into the CeA resulted in anterograde labelling of axons and varicosities throughout the RVLM without retrograde labelling of somata in any brain area. With confocal microscopy, presumptive CeA terminals were found in close apposition to adrenergic (phenylethanolamine-N-methyltransferase-immunoreactive) and non-adrenergic neurones that displayed Fos-immunoreactive nuclei in response to decreased blood pressure. Electron microscopic analysis confirmed that some labelled terminals of CeA axons made synaptic contact with c-fos-activated adrenergic neurones. The results provide evidence that cardiovascular influences elicited from the CeA during stressful events may be mediated, at least in part, via monosynaptic neural projections to barosensitive sympathetic blood pressure-regulating neurones in the RVLM.


Electroreceptive and mechanoreceptive anatomical specialisations in the epaulette shark (Hemiscyllium ocellatum).
The arrangement of the electroreceptive ampullary system and closely related mechanoreceptive lateral line canal system was investigated in the epaulette shark, Hemiscyllium ocellatum. The lateral line canals form an elaborate network across the head and are continuously punctuated by pores. Ampullary pores are distributed in eleven distinct pore fields, and associated ampullary bulbs are aggregated in five independent ampullary clusters on either side of the head. Pores are primarily concentrated around the mouth and across the snout of the animal. We provide the anatomical basis for future behavioural studies on electroreception and mechanoreception in epaulette sharks, as well as supporting evidence that the electroreceptive ampullary system is specialised to provide behaviourally relevant stimuli. In addition, we describe ampullary pores distributed as far posteriorly as the dorsal fin and thus reject the assumption that ampullary pores are restricted to the cephalic region in sharks.


Detection of genetic variation in Ustilago maydis strains by probes derived from telomeric sequences.
Genetic variation using probes derived from telomeric sequences was analysed among several Ustilago maydis strains in an attempt to identify discriminative fingerprint patterns. Three groups of wild isolates from different geographical areas and one group of standard laboratory strains were examined. Analysis of the endmost restriction fragments (EFs) and of the endmost-associated restriction fragments (EAFs) of the chromosomes revealed group differences. Most of the EFs in two groups of strains showed a similar length whereas in the other two groups they were distributed in classes of different lengths. Furthermore, analysis of the EAFs permitted possible fingerprint patterns to be predicted for each group of strains based on the occurrence of amplified bands as well as the presence or absence of distinct bands which were shown to be present in terminal as well as in interstitial sites of the chromosome. The approach evaluated in this work yielded highly polymorphic fingerprint patterns and could be used to distinguish groups of fungal isolates; this approach may also be effective for other fungal systems.


Differential Relationships among Circulating Inflammatory and Immune Activation Biomediators and Impact of Aging and Human Immunodeficiency Virus Infection in a Cohort of Injection Drug Users.
As individuals with human immunodeficiency virus (HIV) infection live longer, aging and age-related chronic conditions have become major health concerns for this vulnerable population. Substantial evidence suggests that chronic inflammation and immune activation contribute significantly to chronic conditions in people aging with or without HIV infection. As a result, increasing numbers of inflammation and immune activation biomediators have been measured. While very few studies describe their in vivo relationships, such studies can serve as an important and necessary initial step toward delineating the complex network of chronic inflammation and immune activation. In this study, we evaluated in vivo relationships between serum levels of neopterin, a biomediator of immune activation, and four commonly described inflammatory biomediators: soluble tumor necrosis factor (TNF)-α receptor (sTNFR)-1, sTNFR-2, interleukin (IL)-6, and C-reactive protein (CRP), as well as the impact of HIV infection and aging in the AIDS Linked to the Intravenous Experience (ALIVE) study, a community-recruited observational study of former and current injection drug users (IDUs) with or at high risk for HIV infection in Baltimore, MD, USA. The study included 1,178 participants in total with 316 HIV-infected (HV+) and 862 HIV-uninfected (HIV-) IDUs. Multivariate regression analyses were employed, adjusting for age, sex, body mass index, smoking, hepatitis C virus co-infection, injection drug use, comorbidities, and HIV status (for all participants), and HIV viral load, CD4+ T-cell counts, and antiretroviral therapy (for HIV+ participants). The results showed significant impact of aging on all five biomediators and that of HIV infection on all but sTNFR-1. In the adjusted model, neopterin had positive associations with sTNFR-1 and sTNFR-2 (partial correlation coefficients: 0.269 and 0.422, respectively, for all participants; 0.292 and 0.354 for HIV+; and 0.262 and 0.435 for HIV-, all p < 0.0001). No significant associations between neopterin and IL-6 or CRP were identified. Such differential relationships between circulating neopterin and sTNFR-1, sTNFR-2, IL-6, and CRP may help inform their selection in future studies. These findings may also facilitate elucidation of underlying inflammatory and immune activation pathways that contribute to age-related chronic conditions, potentially leading to identification of key biomediators, particularly those upstream of CRP, as novel targets for intervention.


[Robotic procedures in the colorectal surgery].
The da Vinci surgical system (Intuitive Surgical, Sunnyvale, CA, USA) was developed specifically to compensate the technical limitations of laparoscopic instruments, such as two-dimensional vision, misalignment of hands and instruments, limited dexterity of instruments inside the patient, and fixed instrument tips. The da Vinci system provides a stable camera platform, three-dimensional imaging, excellent ergonomics, tremor elimination, ambidextrous capability, motion scaling, and instruments with multiple degrees of freedom. These advantages can be applied in the field of colorectal surgery, and that's why we are reporting 45 cases that underwent robotic colorectal surgery. We concluded that the da Vinci system may be useful in surgical procedures, such as splenic flexure takedown, dissection of the inferior mesenteric artery with identification of the nervous plexus, and dissection of a narrow pelvis. The major drawbacks of robotic systems are high cost, and a lack of tactile sensation and tensile feedback to the surgeon, who must depend on visual cues to estimate the tension exerted on tissue by the robotic arms. In conclusion, robotic colorectal surgery can be performed safely and effectively, using the da Vinci surgical system, because this system has more dexterity and flexibility than conventional laparoscopic instruments. However, prospective randomized studies are necessary to evaluate the preservation of sexual and voiding function, as well as the oncological and functional (pelvic floor disorders) outcomes of this approach.


Nauclea latifolia Smith (Rubiaceae) exerts antinociceptive effects in neuropathic pain induced by chronic constriction injury of the sciatic nerve.
The roots of Nauclea latifolia Smith (Rubiaceae) popularly known as "koumkouma" is used in traditional Cameroonian medicine as neuropathic pain remedy and for the treatment of headache, inflammatory pain and convulsion. This study was conducted to evaluate the antinociceptive effects of the alkaloid fraction isolated from Nauclea latifolia in neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve in rat. Bioactive-guided fractionation of the root extracts of Nauclea latifolia using the Von Frey in a rat model of neuropathic pain (Benett model), afforded a potent anti-hyperalgesic fraction IV. Further fractionation of this fraction was performed by high-performance liquid chromatography (HPLC), yielded eight sub-fractions (F1-F8) which were tested for antinociceptive effects. The alkaloid fraction (F3) collected by HPLC, exhibited potent antinociceptive effects, and the anti-allodynic and anti-hyperalgesic effects of this fraction (8, 16, 40 and 80 mg/kg) were determined using the von Frey and acetone tests respectively in a rat model of neuropathic pain. Rota-rod performance and catalepsy tests were used for the assessment of motor coordination. The alkaloid fraction (80 mg/kg) administered intraperitoneally induced a completely decreased hyperalgesia 90 min post-dosing. In the acetone test, the Nauclea latifolia fraction at 80mg/kg showed its maximal anti-allodynic effects 120 min post-injection. The areas under the curve (AUC) of the anti-allodynic or anti-hyperalgesic effects produced by the alkaloid fraction at 80 mg/kg were significantly (p<0.001) greater than the AUC of effects produced by vehicle in CCI rats. The alkaloid fraction did not exhibit any significant effects on the spontaneous locomotor activity of the mice in rota-rod performance and no sign of catalepsy was observed. The analysis of the effects, expressed as the time course of AUC, supports the traditional use of Nauclea latifolia in neuropathic pain therapy. The pharmacological and chemical studies are continuing in order to characterize the mechanism(s) responsible for this anti-hyperalgesic and anti-allodynic action and also to identify the active substances present in the roots extracts of Nauclea latifolia.


Trioctylphosphine-assisted morphology control of ZnO nanoparticles.
This study investigates the morphological change in colloidal ZnO nanoparticles (NPs) synthesized with trioctylphosphine (TOP). The addition of TOP to the synthesis causes an evolution in the shape of ZnO NPs to tadpole-like particles from quasi-spherical particles at 300 °C. The total length of the tadpole-like ZnO NPs can be modified by controlling the molar ratio of TOP to oleylamine (OLAM). The tadpole-like particles are elongated as the concentration of TOP increased but decreased when the addition of TOP is excessive. These tadpole-like ZnO NPs transform to quasi-spherical NPs regardless of the amount of TOP at a reaction time of 3 h at 300 °C. At 200 °C, the effect of TOP on the ZnO NP synthesis differs from that at 300 °C. The ZnO NPs synthesized by controlling the molar ratios of surfactant ligands (TOP:OLAM = 2:100 and 70:100) at 200 °C share similar amorphous structures, while a crystalline ZnO phase is formed when the reaction time is 3 h. X-ray photoelectron spectroscopy analysis shows that TOP influences the oxidation of ZnO and suggests that a combination of OLAM and TOP plays a role in controlling the shape of ZnO NPs. These results provide critical insights to the utilization of TOP for a shape controlling ligand in ZnO NPs and suggest a new route to design oxide NPs.


Eavesdropping Micropredators as Dynamic Limiters of Sexual Signal Elaboration and Intrasexual Competition.
AbstractTo thoroughly understand the drivers of dynamic signal elaboration requires assessing the direct and indirect effects of naturally interacting factors. Here, we use structural equation modeling to test multivariate data from in situ observations of sexual signal production against a model of causal processes hypothesized to drive signal elaboration. We assess direct and indirect effects, and relative impacts, of male-male competition and attacks by eavesdropping frog-biting midges (Diptera: Corethrellidae) on call elaboration of male túngara frogs (Engystomops pustulosus). We find that the intensity of attacks by these micropredator flies drives the extent to which frogs elaborate their calls, likely due to a temporal trade-off between signaling and antimicropredator defense. Micropredator attacks appear to dynamically limit a male's call rate and complexity and consequently dampen the effects of intrasexual competition. In accounting for naturally interacting drivers of signal elaboration, this study presents a counterpoint to the mechanisms traditionally thought to drive sexual selection in this system. Moreover, the results shed light on the relatively unexamined and potentially influential role of eavesdropping micropredators in the evolution of sexual communication systems.


When clinicians and a parent disagree on the extent of medical care.
TG is a 32-month-old girl with a rare lysosomal storage disease. The diagnosis was confirmed at 8 months of age; she underwent bone marrow transplant at 14 months. TG's father remained at home with her siblings whereas her mother lived at the transplant hospital with TG for 1 year. Significant respiratory infections led to dependency on a tracheotomy and ventilator. She was transferred to the current hospital 10 months ago for respiratory rehabilitation, which has been complicated by pulmonary hemorrhages. On examination, TG was in a wheelchair with truncal support and leg splints. She is a small child with coarse facial features, generalized hypotonia, and significant joint restriction. She exhibited intermittent repetitive arm movements. A tracheotomy was in place, and she did not vocalize. Variable levels of alertness were observed although she rarely signaled to others for social engagement or to express her needs. Eye contact was limited and she responded inconsistently to her name. TG's mother states that her daughter interacts well with her and uses a number of signs for communication. The rehabilitation staff reported limited progress and recommends withdrawal of services. TG's mother expressed frustration with her daughter's poor developmental improvement and believes she needs more intensive therapy, not less. Staff members are now frustrated with TG's mother's level of involvement with her daughter's care. Although TG's mother spends full weekdays at her daughter's bedside, she is often working on her computer managing her business. TG's father works full time and visits on the weekends, when her mother returns home. TG's mother has expressed frustration with her daughter's level of improvement; she believes TG needs more intensive therapy that the hospital is not providing. She informed the staff that other children with this type of storage disease may have delays, but are often higher functioning. TG's mother made the point to the staff that the family's reason for pursuing a bone marrow transplant was to attempt to correct the enzyme deficiency and improve her daughter's outcome.


Incorporating gene co-expression network in identification of cancer prognosis markers.
Extensive biomedical studies have shown that clinical and environmental risk factors may not have sufficient predictive power for cancer prognosis. The development of high-throughput profiling technologies makes it possible to survey the whole genome and search for genomic markers with predictive power. Many existing studies assume the interchangeability of gene effects and ignore the coordination among them. We adopt the weighted co-expression network to describe the interplay among genes. Although there are several different ways of defining gene networks, the weighted co-expression network may be preferred because of its computational simplicity, satisfactory empirical performance, and because it does not demand additional biological experiments. For cancer prognosis studies with gene expression measurements, we propose a new marker selection method that can properly incorporate the network connectivity of genes. We analyze six prognosis studies on breast cancer and lymphoma. We find that the proposed approach can identify genes that are significantly different from those using alternatives. We search published literature and find that genes identified using the proposed approach are biologically meaningful. In addition, they have better prediction performance and reproducibility than genes identified using alternatives. The network contains important information on the functionality of genes. Incorporating the network structure can improve cancer marker identification.


Personalized, bilateral whole-body somatosensory cortex stimulation to relieve fatigue in multiple sclerosis.
The patients suffering from multiple sclerosis (MS) often consider fatigue the most debilitating symptom they experience, but conventional medicine currently offers poorly efficacious therapies. We executed a replication study of an innovative approach for relieving MS fatigue. According to the sample size estimate, we recruited 10 fatigued MS patients who received 5-day transcranial direct current stimulation (tDCS) in a randomized, double-blind, Sham-controlled, crossover study, with modified Fatigue Impact Scale (mFIS) score reduction at the end of the treatment as primary outcome. A personalized anodal electrode, shaped on the magnetic resonance imaging (MRI)-derived individual cortical folding, targeted the bilateral whole-body primary somatosensory cortex (S1) with an occipital cathode. The amelioration of fatigue symptoms after Real stimulation (40% of baseline) was significantly larger than after Sham stimulation (14%, p = 0.012). Anodal whole body S1 induced a significant fatigue reduction in mildly disabled MS patients when the fatigue-related symptoms severely hampered their quality of life. This second result in an independent group of patients supports the idea that neuromodulation interventions that properly select a personalized target might be a suitable non-pharmacological treatment for MS fatigue.


New developments on drug treatment rehabilitation.
Increasing interest has been directed to role of pharmaceuticals in the recovery of cerebrovascular events. However, only few scientific studies are available to date, and further research is needed. Amphetamine is the most extensively studied drug shown to promote recovery of function, although clinical data have lead to conflicting results. Other psychostimulants drugs have been proposed, as levodopa or methylphenidate, even if published data are still few. Recently, two studies have been published about the positive role of cholinesterase inhibitor donepezil on stroke recovery. However, such data must still be confirmed by randomized controlled trials. Antidepressant drugs have shown to be effective not only in improving depressive symptoms in stroke patients, but also in decreasing, although partially, the negative impact of poststroke depression on functional outcome. Serotoninergic agents may have a role in improving stroke recovery, in a fashion that is not dependent on their primary antidepressant activity. Last, it is important to be aware that certain drugs as clonidine, prazosin, dopamine receptor antagonists, benzodiazepines, phenytoin, and phenobarbital could have a detrimental effect on the poststroke recovery.


Anomalous Shape Evolution of Ag2O2 Nanocrystals Modulated by Surface Adsorbates during Electron Beam Etching.
An understanding of nanocrystal shape evolution is significant for the design, synthesis, and applications of nanocrystals with surface-enhanced properties such as catalysis or plasmonics. Surface adsorbates that are selectively attached to certain facets may strongly affect the atomic pathways of nanocrystal shape development. However, it is a great challenge to directly observe such dynamic processes in situ with a high spatial resolution. Here, we report the anomalous shape evolution of Ag2O2 nanocrystals modulated by the surface adsorbates of Ag clusters during electron beam etching, which is revealed through in situ transmission electron microscopy (TEM). In contrast to the Ag2O2 nanocrystals without adsorbates, which display the near-equilibrium shape throughout the etching process, Ag2O2 nanocrystals with Ag surface adsorbates show distinct facet development during etching by electron beam irradiation. Three stages of shape changes are observed: a sphere-to-a cube transformation, side etching of a cuboid, and bottom etching underneath the surface adsorbates. We find that the Ag adsorbates modify the Ag2O2 nanocrystal surface configuration by selectively capping the junction between two neighboring facets. They prevent the edge atoms from being etched away and block the diffusion path of surface atoms. Our findings provide critical insights into the modulatory function of surface adsorbates on the shape control of nanocrystals.


Genetic fate mapping of Olig2 progenitors in the injured adult cerebral cortex reveals preferential differentiation into astrocytes.
Olig2 is a basic helix-loop-helix (bHLH) transcription factor essential for development of motoneurons and oligodendrocytes. It is known that Olig2(+) cells persist in the central nervous system (CNS) from embryonic to adult stages and that the number of Olig2(+) progenitors increases in the injured adult CNS. Recent studies have demonstrated an inhibitory action of Olig2 on neurogenesis in adult CNS, but the fate of Olig2(+) cells in the injured state remains largely unknown. To trace directly the fate of Olig2 cells in the adult cerebral cortex after injury, we employed the CreER/loxP system to target the olig2 locus. In this genetic tracing study, green fluorescent protein (GFP) reporter-positive cells labeled after cryoinjury coexpressed glial fibrillary acidic protein (GFAP), an astrocytic marker. Electron microscopy also showed that GFP(+) cells have the ultrastructural characteristics of astrocytes. Furthermore, GFP(+) cells labeled before injury, most of which had been NG2 cells, also produced bushy astrocytes. Here we show direct evidence that Olig2(+) cells preferentially differentiate into astrocytes, which strongly express GFAP, in response to injury in the adult cerebral cortex. These results suggest that reactive astrocytes, known to be the main contributors to glial scars, originate, at least in part, from Olig2(+) cells.


Combined Conventional and Endoscopic Microdebrider-Assisted Adenoidectomy: A Tertiary Centre Experience.
Adenoidectomy is one of the most commonly performed surgical procedures in children. Conventional adenoidectomy is associated with incomplete adenoid tissue removal with persistence of symptoms. The advent of rigid nasal endoscopes, cold light source, fiber optics and powered instruments used in functional endoscopic sinus surgery helped in the development of endoscopic microdebrider-assisted adenoidectomy. To establish the safety and efficacy of combined conventional and endoscopic microdebrider-assisted adenoidectomy procedure. This is a prospective study of 60 child patients who underwent combined conventional and endoscopic microdebrider-assisted adenoidectomy. The study was conducted from September 2013 to September 2015. Only child patients with grade 3 and grade 4 Adenoid Hypertrophy (AH) was included in the study. At the end of conventional adenoidectomy and after combined procedure, the AH was graded again. Post-operative complications like neck pain, hypernasality and swallowing problems were noted. Their symptom score was reviewed before surgery and after one month and one year of surgery. The duration of surgery and amount of blood loss was recorded. By this technique, complete clearance of adenoid tissue was obtained in all 60 (100%) cases. The mean pre-operative symptom score for AH was 3.7, which improved to 0 after one month of combined conventional and endoscopic microdebrider-assisted adenoidectomy. All child patients were symptom-free at the end of one month and one year. The duration of conventional adenoidectomy was 5 minutes 12 seconds while total duration of the combined conventional and endoscopic microdebrider-assisted adenoidectomy was 14 minutes 45 seconds. There was no significant blood loss (15±3 ml approximately). There were no major complications in this study. The combined approach of conventional curette along with endoscopic microdebrider-assisted adenoidectomy is a safe and effective method for complete and accurate removal of large adenoids.


Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers.
Notch ligands signal through one of four receptors on neighboring cells to mediate cell-cell communication and control cell fate, proliferation, and survival. Although aberrant Notch activation has been implicated in numerous malignancies, including breast cancer, the importance of individual receptors in distinct breast cancer subtypes and the mechanisms of receptor activation remain unclear. Using a novel antibody to detect active NOTCH3, we report here that NOTCH3 signals constitutively in a panel of basal breast cancer cell lines and in more than one third of basal tumors. Selective inhibition of individual ligands revealed that this signal does not require canonical ligand induction. A NOTCH3 antagonist antibody inhibited growth of basal lines, whereas a NOTCH3 agonist antibody enhanced the transformed phenotype in vitro and in tumor xenografts. Transcriptomic analyses generated a Notch gene signature that included Notch pathway components, the oncogene c-Myc, and the mammary stem cell regulator Id4 This signature drove clustering of breast cancer cell lines and tumors into the common subtypes and correlated with the basal classification. Our results highlight an unexpected ligand-independent induction mechanism and suggest that constitutive NOTCH3 signaling can drive an oncogenic program in a subset of basal breast cancers. Cancer Res; 77(6); 1439-52. ©2017 AACR.


Associations among Socioeconomic Factors, Lag Time, and High-Risk Histopathologic Features in Eyes Primarily Enucleated for Retinoblastoma.
Purpose/Aim: To determine the associations among socioeconomic factors, delay in management, and high-risk histopathologic features in eyes primarily enucleated for retinoblastoma. Materials and Methods: A single-site survey was conducted from January 2016 through January 2018. Eyes primarily enucleated for unilateral retinoblastoma were reviewed for the presence of high-risk histopathologic features. Information on clinical characteristics, socioeconomic factors, and lag time were collected during hospitalization. Results: Of the 138 children analyzed, 60 (43.5%) carried high-risk histopathologic features. Compared to children with a standard risk, those with a high risk had a longer median lag time before treatment (21.5 vs 15.0 days, P = .007), but their overall lag time (54.0 vs 50.0 days, P = .062) and delay in the initial visit (7.0 vs 10.0 days, P = .782) were comparable. Logistic regression analysis showed that children with a lag time ≥ 30 days were at a significantly higher risk of extraocular invasion (odds ratio [OR] = 2.38 and 95% confidence interval [CI] = 1.08-5.37 for treatment delay; OR = 2.12 and 95% CI = 1.01-4.62 for overall delay). Neither high-risk histopathologic features nor lag time was associated with any demographic or major socioeconomic factors, including sex, age at diagnosis or enucleation, ethnicity, household income, parents' education level, medical insurance coverage, and left-behind status. Conclusions: For children with advanced unilateral retinoblastoma, there is no statistical difference in overall lag time between standard and high-risk groups. Major socioeconomic parameters have little impact on the delay and histopathologic outcomes, thus implying that children with varied socioeconomic status may be at a similar risk of advanced tumor invasion.


Restoring cerebral blood flow reveals neural regions critical for naming.
We identified areas of the brain that are critical for naming pictures of objects, using a new methodology for testing which components of a network of brain regions are essential for that task. We identified areas of hypoperfusion and structural damage with magnetic resonance perfusion- and diffusion-weighted imaging immediately after stroke in 87 individuals with impaired picture naming. These individuals were reimaged after 3-5 d, after a subset of patients underwent intervention to restore normal blood flow, to determine areas of the brain that had reperfused. We identified brain regions in which reperfusion was associated with improvement in picture naming. Restored blood flow to left posterior middle temporal/fusiform gyrus, Broca's area, and/or Wernicke's area accounted for most acute improvement after stroke. Results show that identifying areas of reperfusion that are associated with acute improvement of a function can reveal the brain regions essential for that function.


Pulmonary veno-occlusive disease.
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH) characterised by preferential remodelling of the pulmonary venules. In the current PH classification, PVOD and pulmonary capillary haemangiomatosis (PCH) are considered to be a common entity and represent varied expressions of the same disease. The recent discovery of biallelic mutations in the EIF2AK4 gene as the cause of heritable PVOD/PCH represents a major milestone in our understanding of the molecular pathogenesis of PVOD. Although PVOD and pulmonary arterial hypertension (PAH) share a similar clinical presentation, with features of severe precapillary PH, it is important to differentiate these two conditions as PVOD carries a worse prognosis and life-threatening pulmonary oedema may occur following the initiation of PAH therapy. An accurate diagnosis of PVOD based on noninvasive investigations is possible utilising oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest. No evidence-based medical therapy exists for PVOD at present and lung transplantation remains the preferred definitive therapy for eligible patients.


Alcohol oxidase expressed under nonmethylotrophic conditions is imported, assembled, and enzymatically active in peroxisomes of Hansenula polymorpha.
We have introduced into Hansenula polymorpha an extra copy of its alcohol oxidase gene. This gene which is under the control of the Saccharomyces cerevisiae phosphoglycerate kinase promoter is integrated in a chromosome different from the one containing the endogenous gene. Cells with the extra alcohol oxidase gene, grown on glucose or ethanol as the sole carbon source, express enzymatically active alcohol oxidase. However, other enzymes characteristic for methylotrophic growth conditions are absent or present at low levels. Most of the alcohol oxidase occurs in the octameric state and immuno- and cytochemical evidence shows that it is located in a single enlarged peroxisome per cell. Such peroxisomes show crystalloid inclusions which are lacking in the peroxisomes present in glucose grown control cells. Our results suggest that import into peroxisomes of H. polymorpha, assembly and activation of alcohol oxidase is not conditionally dependent on adaptation to methylotrophic growth conditions and that proliferation of peroxisomes is a well-programmed process that is not triggered solely by overproduction of a peroxisomal protein.


Use of beta-methasone in management of preterm gestation with premature rupture of membranes.
Use of corticosteroids in the management of rupture of the membranes in a preterm gestation was evaluated. Ninety-three mothers (105 infants) received beta-methasone, whereas 105 mothers (112 infants) did not. The incidence of significant neonatal respiratory complications was statistically higher for beta-methasone-treated (26.6%) compared with non-treated patients (11.1%) who delivered more than 48 hours after rupture of membranes. Neonatal septic complications also were significantly higher in treated (21.3%) than in nontreated (9.2%) patients delivered 48 hours after rupture of membranes. Maternal sepsis was not statistically different between the two groups. In the nonsteroid-treated patients, the incidence of significant respiratory distress syndrome was greater for those infants delivered within 48 hours (31.0%) than those delivered more than 48 hours (11.1%) from rupture of membranes. The data support conservative management and indicate that corticosteroid administration in a preterm gestation with rupture of membranes is not beneficial to the newborn.


Comparative study on reduction of bone loss and lipid metabolism abnormality in ovariectomized rats by soy isoflavones, daidzin, genistin, and glycitin.
The effects of the soy isoflavone glycoside, daidzin, genistin, and glycitin on bone loss and lipid metabolism in ovariectomized (ovx) rats were compared with those of estrone. Thirty-six 11-week-old female Sprague-Dawley rats were assigned to six groups, sham-operated, ovx, ovx+glycitin, ovx+daidzin, ovx+genistin, and ovx+estrone and fed matched amounts of a commercial calcium-deficient diet for 4 weeks. Throughout this period, daidzin, genistin or glycitin (25, 50 or 100 mg/kg/d) was given orally using a stomach tube, or estrone (7.5 microg/kg/d) was administered subcutaneously. Daidzin, genistin and glycitin significantly prevented bone loss in ovx rats at a dose of 50 mg/kg/d, like estrone. At this dose glycitin and daidzin also prevented ovx-induced uterine atrophy and increases in body weight gain, abdominal fat, serum total cholesterol and triglyceride, and urinary excretion of pyridinoline and deoxypyridinoline with statistical significance, like estrone. On the other hand, genistin prevented ovx-induced uterine atrophy only at a dose of 100 mg/kg, but did not block any other change of ovx rats at a dose of 50 or 100 mg/kg. These findings indicate that daidzin, glycitin, and genistin are effective in preventing bone loss and the former two compounds are effective in reversing the unfavorable changes of lipid metabolism in this model. It is suggested that the preventive effect of daidzin or glycitin on bone loss in ovx rats is due to suppression of bone turnover, as in the case of estrone, but genistin has a different mechanism of action from the other compounds. Soy isoflavone glycosides may represent a potential alternative therapy in the treatment of bone loss and lipid metabolism abnormality in ovarian hormone-deficient women.


Use of clozapine in older Asian patients with schizophrenia between 2001 and 2009.
To date there has been no large-scale international study that examined the use of clozapine in older patients with schizophrenia. This study examined the use of clozapine and its demographic and clinical correlates in older patients with schizophrenia in East Asia during the period between 2001 and 2009. Information on 1,157 hospitalized patients with schizophrenia aged 50 or older in five East Asian countries and territories (China, Hong Kong, Korea, Singapore and Taiwan) was extracted from the database of the Research on Asian Psychotropic Prescription Patterns (REAP) project. Socio-demographic and clinical characteristics and prescription of psychotropic medications were recorded. Clozapine was prescribed for 20.6% of the pooled sample; 19.0% in 2001, 19.4% in 2004 and 22.9% in 2009. Multiple logistic regression analysis of the whole sample revealed that patients taking clozapine had a longer duration of illness, more negative symptoms and were less likely to receive first generation antipsychotic and anticholinergic drugs, but more likely to report weight gain compared to those not receiving clozapine. Compared to those in other sites, older patients in China were more likely to receive clozapine. The prescription of clozapine for older Asian schizophrenia inpatients has remained at a stable level during the past decade. The appropriateness of use of clozapine in China needs to be further explored.


A novel bulk-culture method for generating mature dendritic cells from mouse bone marrow cells.
We established a novel culture method for generating dendritic cells (DC) from mouse bone marrow (BM) cells. Unfractionated bulk BM cells were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 5-7 days and a DC population was isolated by gradient centrifugation with 14.5% (w/v) metrizamide. Through this method, 30-40 x 10(6)/mouse DC with 85-95% purity was obtained on day 7; this yield was higher than those of conventional DC generated by Inaba's method either with GM-CSF alone (conventional-GM DC) or GM-CSF and IL-4 (conventional-GM/4 DC). Bulk-cultured DC have a more matured phenotype than both conventional-GM and -GM/4 DC as shown by higher expression of CD86, MHC class II and CD40. Functional analyses reveal that (1) bulk-DC show less ability in endocytosis than conventional-GM DC and are comparable in IL-12 p70 production with conventional-GM and -GM/4 DC. (2) Bulk-DC exhibit stronger stimulatory capacity in allogeneic T-cell proliferation than conventional DC. (3) By using ovalbumin (OVA) and OVA-specific T-cell receptor (TCR) transgenic mice (DO11.10) system, OVA protein-loaded bulk-DC stimulated CD4 T cells of DO11.10 mice more than conventional-GM DC and comparable with conventional-GM/4 DC. (4) Furthermore, OVA peptide-pulsed bulk-DC stimulated CD4 T cells more than conventional-GM and -GM/4 DC. These data indicate that bulk-DC are functionally more mature than conventional DC. Taken together, bulk-culture method is a simple technique for generating functionally mature BM-DC in large quantities and high purity.


Urbanization and the temporal patterns of social networks and group foraging behaviors.
Urbanization causes dramatic and rapid changes to natural environments, which can lead the animals inhabiting these habitats to adjust their behavioral responses. For social animals, urbanized environments may alter group social dynamics through modification of the external environment (e.g., resource distribution). This might lead to changes in how individuals associate or engage in group behaviors, which could alter the stability and characteristics of social groups. However, the potential impacts of urban habitat use, and of habitat characteristics in general, on the nature and stability of social associations remain poorly understood. Here, we quantify social networks and dynamics of group foraging behaviors of black-capped chickadees (N = 82, Poecile atricapillus), at four urban and four rural sites weekly throughout the nonbreeding season using feeders with radio frequency identification of individual birds. Because anthropogenic food sources in urban habitats (e.g., bird feeders) provide abundant and reliable resources, we predicted that social foraging associations may be of less value in urban groups, and thus would be less consistent than in rural groups. Additionally, decreased variability of food resources in urban habitats could lead to more predictable foraging patterns (group size, foraging duration, and the distribution of foraging events) in contrast to rural habitats. Networks were found to be highly consistent through time in both urban and rural habitats. No significant difference was found in the temporal clumping of foraging events between habitats. However, as predicted, the repeatability of the clumping of foraging events in time was significantly higher in urban than rural habitats. Our results suggest that individuals living in urban areas have more consistent foraging behaviors throughout the nonbreeding season, whereas rural individuals adjust their tactics due to less predictable foraging conditions. This first examination of habitat-related differences in the characteristics and consistency of social networks along an urbanization gradient suggests that anthropic habitat use results in subtle modifications in social foraging patterns. Future studies should examine potential implications of these differences for variation in predation risk, energy intake, and information flow.


Mutagenesis induced by oral carcinogens in lacZ mouse (MutaMouse) tongue and other oral tissues.
Animal models for carcinogenesis of the oral cavity are limited, although this disease is often fatal or disfiguring and its incidence in the USA is approximately 30 000 cases/year. Short-term whole-animal models for this disease should prove valuable in the investigation of factors affecting oral carcinogenesis. In this study we observed that a group of oral carcinogens are clearly mutagenic in the lacZ transgenic mouse oral cavity. The carcinogens 4-nitroquinoline-N-oxide (4-NQO), benzo[a]pyrene (B[a]P), N-nitroso-N-methylurea (NMU), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), nitrosonornicotine (NNN) and 7,12-dimethylbenzanthracene (DMBA) were all mutagenic in a mixture of pooled oral tissues (gingival, buccal, pharyngeal and sublingual) and in the tongue. All agents except DMBA (which was swabbed in the oral cavity) and B[a]P (by gavage) were given in drinking water for 2-4 weeks followed by a 2 week expression period before killing. With one exception, groups of 4-5 female mice were treated. The doses and mutant fractions (MF) in DNA isolated from pooled oral tissues (in mutants/10(5) p.f.u. +/- SD) were: 4-NQO (20-80 microg/ml, over 4 weeks) 78 +/- 16; B[a]P (five doses of 125 mg/ml) 33.2 +/- 10.9; NMU (20-80 microg/ml over 4 weeks) 7.8 +/- 2.6; NNK (0.1 mg/ml, weeks 1-2, 0.2 mg/ml, weeks 3-4) 9.1 +/- 3.0; NNN (same dose as NNK) 9.2 +/- 1.6 and DMBA (0.5 mg/ml in corn oil, 3 weeks) 7.1 +/- 2.7. The corresponding value for untreated controls was 3.2 +/- 1.8. Values for induced mutagenesis in tongue from the same animals were similar except for 4-NQO which was about twice as potent in tongue. Mutagenesis by several compounds was compared in other organs. B[a]P was assayed in lung and kidney and was about twice as mutagenic in oral tissues as in lung, but several times less mutagenic in kidney. Lung, but not kidney is a target organ for B[a]P-induced carcinogenesis in the mouse. NNK was somewhat more mutagenic in lung (MF of 15.0 +/- 5.5) than in oral tissues, corresponding with previous reports on carcinogenesis by NNK. Mutagenesis induced by NNN was also assayed in esophagus, a target organ in rodents, and was similar to that in oral tissue. In all cases the MF in untreated control group was about 3-4. These results suggest that: (i) the oral cavity has a significant capacity for metabolic activation of carcinogens; (ii) DNA damage in the oral cavity can be converted to mutations; and (iii) there is significant target organ specificity. The results also tend to support the concept that the anatomical components of the upper aerodigestive tract, in general, behave similarly with respect to genotoxicity. As carcinogenesis is believed to involve mutagenesis, this study demonstrates the utility of the lacZ mouse for investigations involving initiation of carcinogenesis of the oral cavity.


Prevalence of self-reported hypertension and its relation to dietary habits, in adults; a nutrition & health survey in Greece.
Hypertension leads to many degenerative diseases, the most common being cardiovascular in origin. This study has been designed to estimate the prevalence of self-reported hypertension in a random nationwide sample of adult Greek population, while focus was set to the assessment of participants' nutritional habits in relation to their hypertension status. A random-digit dialed telephone survey. Based on a multistage, stratified sampling, 5003 adults (18 - 74 yr) participated (men: 48.8%, women: 51.2%). All participants were interviewed via telephone by trained personnel who used a standard questionnaire. The questionnaire included demographic and socioeconomic characteristics, medical history, lifestyle habits and nutritional assessment. The prevalence of self-reported hypertension was 13.3% in men and 17.7% in women (P < 0.001). Furthermore, women reported higher values of systolic blood pressure (180 +/- 27 mmHg) than men (169 +/- 24 mmHg). Positive relationships were found between hypertension status and the prevalence of the rest investigated health conditions (i.e. hypercholesterolaemia, diabetes mellitus, renal failure and obesity). Nutritional assessment showed that consumption of fish, fruits and juices, cereals, and low fat milk and yogurt was significantly higher among hypertensive subjects while the opposite was observed for food items as red meat, pork, egg, pasta and rice, full fat dairy products and desserts. Hypertension seems to be a serious public health problem in Greece. It is encouraging that hypertensives may have started adopting some more healthy nutritional behaviour compared to normotensive ones. However, they can gain significant benefits regarding to blood pressure control, if they increase the level of compliance with dietary recommendations.


Culture substrates made of elastomeric micro-tripod arrays for long-term expansion of human pluripotent stem cells.
Culturing and expansion of human pluripotent stem cells (hPSCs) depend on the chemical and physical properties of the substrates. Gel-coated substrates providing low stiffness are commonly used for long-term pluripotency maintenance of hPSCs. We previously reported that gelatin nanofibrous substrates also allow long-term culturing of hPSCs, suggesting the importance of three-dimensional (3D) organization of extracellular matrix proteins. To further evaluate the significance of 3D features and material stiffness, we fabricated elastomeric micro-tripod arrays (MTAs) and maintained hPSC propagation over 10 passages without observing the pluripotency loss or the development of chromosomal abnormality. We also found that the hPSC colonies on MTAs were more rounded than those on gel-coated flat substrates. Theoretical analyses suggested that the effective stiffness of elastomeric MTAs is comparable to that of gel-coated substrates and that the effect of structural anisotropy is negligible. Cells on MTAs benefit from enhanced diffusion underneath the hPSC colonies as well as enzyme-free detachment from the substrate during passage.


Siderophore-mediated signaling regulates virulence factor production in Pseudomonasaeruginosa.
Numerous bacteria secrete low molecular weight compounds termed siderophores that have a high affinity for iron ions. Siderophores have a well-documented role as iron-scavenging chemicals, chelating iron ions in the environment whereupon the ferrisiderophores reenter the bacterial cells by means of specific cell-surface receptors. The iron is then released for incorporation into bacterial proteins. Here we show that in addition to its role as an iron-scavenger, the siderophore pyoverdine that is secreted by Pseudomonas aeruginosa regulates the production of at least three virulence factors (exotoxin A, an endoprotease, and pyoverdine itself), which are major contributors to the ability of this bacterium to cause disease. Regulation occurs through a transmembrane signaling system that includes an outer membrane receptor for ferripyoverdine, a signal-transducing protein that is predicted to extend from the periplasm into the cytoplasm, and a sigma factor. Expression of genes that form part of the regulon is triggered by pyoverdine so that this siderophore acts as a signaling molecule to control the production of secreted products. Recognition that a siderophore acts as a signaling molecule has important implications for the understanding of interactions between bacterial cells.


Proteomics and phosphoproteomics of chordoma biopsies reveal alterations in multiple pathways and aberrant kinases activities.
Chordoma is a slow-growing but malignant subtype of bone sarcoma with relatively high recurrence rates and high resistance to chemotherapy. It is urgent to understand the underlying regulatory networks to determine more effective potential targets. Phosphorylative regulation is currently regarded as playing a significant role in tumorigenesis, and the use of tyrosine kinase inhibitors in clinical practice has yielded new promise for the treatment of a variety of sarcoma types. We performed comprehensive proteomic and phosphoproteomic analyses of chordoma using four-dimensional label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis. The potential aberrantly expressed kinases and their functions were validated using western blotting and CCK-8 assays. Compared with paired normal muscle tissues, 1,139 differentially expressed proteins (DEPs) and 776 differentially phosphorylated proteins (DPPs) were identified in chordoma tumor tissues. The developmentally significant Wnt-signaling pathway and oxidative phosphorylation were aberrant in chordoma. Moreover, we predicted three kinases (AURA, CDK9, and MOK) with elevated activity by kinase-pathway network analysis (KiPNA) and verified their increased expression levels. The knockdown of these kinases markedly suppressed chordoma cell growth, and this was also the case for cells treated with the CDK9 inhibitor AZD4573. We additionally examined 208 proteins whose expression and phosphorylation levels were synergetically altered. We herein depicted the collective protein profiles of chordomas, providing insight into chordomagenesis and the potential development of new therapeutic targets.


Clinical effect of hormonal replacement therapy with estradiol associated with noretisterone or drospirenone. A prospective randomized placebo controlled study.
The study was performed to compare the clinical effect of a hormone replacement therapy (HRT) with two different progestins. Postmenopausal women (PMW) with climacteric symptoms (CS) randomly received for 12 months orally, either placebo (n = 20), 1 mg estradiol (E) plus 0.5 mg noretisterone acetate (NETA; n = 40), or 2 mg drospirenone (DRSP; n = 40), a testosterone- and spironolactone-derived molecule, respectively. Weight (W) declined only during E/DRSP (p < 0.04 versus placebo). Fat mass (FM) decreased, similarly, during E/NETA and E/DRSP. Intracellular water (ICW) did not change, while extracellular water (ECW) decreased during E/DRSP (p < 0.0001) (p < 0.002 versus E/NETA). During E/NETA and E/DRSP, similar decreases were observed for insulin resistance (IR) by the homeostatic model assessment for IR (HOMA-IR) (p < 0.0001 versus placebo for both), systolic (p < 0.04 versus placebo for both) and diastolic (p < 0.002) blood pressure (BP). Lipids did not change. In comparison to placebo CS, by the Kupperman Index (KI), significantly declined (p < 0.0001) during E/NETA or E/DRSP. Menopause-specific Quality of Life (MENQoL) significantly declined versus placebo (p < 0.04) during both E/NETA and E/DRSP. In conclusion, differences between the two progestins are mainly limited to body composition (BC), where the addition of DRSP decreases ECW and body W (BW).


Loss of Myosin Vb in colorectal cancer is a strong prognostic factor for disease recurrence.
Selecting the most beneficial treatment regimens for colorectal cancer (CRC) patients remains challenging due to a lack of prognostic markers. Members of the Myosin family, proteins recognised to have a major role in trafficking and polarisation of cells, have recently been reported to be closely associated with several types of cancer and might thus serve as potential prognostic markers in the context of CRC. We used a previously established meta-analysis of publicly available gene expression data to analyse the expression of different members of the Myosin V family, namely MYO5A, 5B, and 5C, in CRC. Using laser-microdissected material as well as tissue microarrays from paired human CRC samples, we validated both RNA and protein expression of Myosin Vb (MYO5B) and its known adapter proteins (RAB8A and RAB25) in an independent patient cohort. Finally, we assessed the prognostic value of both MYO5B and its adapter-coupled combinatorial gene expression signatures. The meta-analysis as well as an independent patient cohort study revealed a methylation-independent loss of MYO5B expression in CRC that matched disease progression. Although MYO5B mutations were identified in a small number of patients, these cannot be solely responsible for the common downregulation observed in CRC patients. Significantly, CRC patients with low MYO5B expression displayed shorter overall, disease-, and metastasis-free survival, a trend that was further reinforced when RAB8A expression was also taken into account. Our data identify MYO5B as a powerful prognostic biomarker in CRC, especially in early stages (stages I and II), which might help stratifying patients with stage II for adjuvant chemotherapy.


Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians.
To review data on the long-term effects of prenatal exposure to the diabetic intrauterine environment in the Pima Indians of Arizona. This population has high rates of Type 2 diabetes mellitus that has a strong genetic component and develops at young ages. Since 1965, Pima Indians at least 5 years old participated in a study of diabetes and its complications. This study consisted of biennial examinations with measurements of obesity and glucose tolerance and of glucose tolerance testing during pregnancy. The longitudinal nature of the study has permitted comparisons of data collected on children and young adults whose mothers were tested during pregnancy. Offspring of women who had diabetes during pregnancy were more obese and had a higher prevalence of Type 2 diabetes. Exposure to the diabetic intrauterine environment was responsible for about 40% of Type 2 diabetes in 5-19-year-old children between 1987 and 1996--approximately twice the attributable risk found between 1967 and 1976. Over 70% of persons with prenatal exposure have Type 2 diabetes at 25-34 years of age. The effects of the diabetic pregnancy can be thought of as a vicious cycle, with consequences for the offspring extending well beyond the neonatal period. The young woman whose mother had diabetes during pregnancy is at risk of perpetuating the cycle by developing diabetes by her childbearing years. In this population, much of the increase in childhood Type 2 diabetes can be attributed to the diabetic intrauterine environment, which may be a factor in the alarming rise of this disease nationally.