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20439080

Comparison of HIV DNA and RNA in gut-associated lymphoid tissue of HIV-infected controllers and noncontrollers

Objectives:HIV-infected controllers have provided novel insights into mechanisms of viral control. We investigated the degree to which HIV DNA and RNA are present in gut-associated lymphoid tissue (GALT) of controllers. Design:Cross-sectional cohort study. Methods:Colorectal biopsy pieces were obtained from five untreated noncontrollers, five ART-suppressed patients, and nine untreated controllers. Results:Rectal HIV DNA was lower in controllers (median 496 copies/106 CD4+ T cells) than in untreated noncontrollers (117483 copies/106 CD4+ T cells, P = 0.001) and ART-suppressed patients (6116 copies/106 CD4+ T cells, P = 0.004). Similarly, rectal HIV RNA was lower in controllers (19 copies/106 CD4+ T cells) than in noncontrollers (15210 copies/106 CD4+ T cells, P = 0.001) and ART-suppressed patients (1625 copies/106 CD4+ T cells, P = 0.0599). Rectal HIV RNA/DNA ratios were not statistically different between the three groups. Conclusion:Despite being able to maintain very low plasma HIV RNA levels in the absence of antiretroviral therapy (ART), HIV-infected controllers have readily measurable levels of HIV DNA and RNA in GALT. As expected, controllers had lower rectal HIV DNA and RNA compared with untreated noncontrollers and ART-suppressed individuals. Compared with the mechanisms of ‘natural’ viral control of controllers, long-term ART does not reduce the total HIV reservoir to the level of controllers.

HIV Infections

immunology

29888582

The diagnostic value of detection of CD20 positive infiltrates in renal biopsies with acute allograft rejection: a pilot study.

INTRODUCTION The recognition of antibody mediated rejection has led to re-appreciation of the role of B cells in acute and chronic allograft rejection. The presence of CD20 positive lymphocytic infiltrates in acute cellular rejection has been associated with poor clinical outcomes and reduced graft survival. Recently molecular gene analysis has shown that grafts with antibody-mediated rejection (ABMR) have lower expression of CD20. METHODS We reviewed 28 renal allograft biopsies, including 13 biopsies from patients who experienced acute ABMR and a matched group of 15 patients with acute T cell mediated rejection (TCMR) to serve as controls. All biopsies were stained by anti-CD20 and anti-CD8 antibodies. RESULTS All twenty-eight biopsies were found to have CD20 positive cells within their interstitial infiltrate. The distribution of CD20 positive cells varied from sparse cells to small or dense clusters in the interstitium. We found no statistically significant differences in CD20 or CD8 cell counts between the ABMR and TCMR groups. We noticed a weak positive correlation between the numbers of CD20 positive cells and the grade/severity of rejection but it didn't reach statistical significance (r=0.37, p=0.06). However, we found a significant positive correlation between the number of CD20 positive cells and intimal artertitis score (r=0.39, p < 0.05). CONCLUSION Our findings suggest that there is a possible relation between the presence of CD20 positive lymphocytic infiltrates and a more severe histological form of rejection. However, we failed to establish a relationship between their actual presence in the interstitial infiltrate and distinct mechanisms of graft rejection.

Kidney

pathology

23520543

[Antioxidant minerals and vitamins. Role in cancer prevention].

Cancer is a disease of the genome and free-radicals can damage genomic DNA, hence the interest in the potential protective antioxidant effect of vitamin and minerals. Indeed, the findings of most retrospective studies suggest that diets rich in fruits and vegetables have a protective effect against cancer. Prospective randomized trials have however given controversial results. Beta-carotene, the precursor of vitamin A has been shown to induce regression of precancerous lesions and 13-cis retinoic acid has a preventive effect on the development of a second cancer in patients with epidermoid cancer of the buccal cavity, the pharynx or the larynx although no effect has been observed on the primary cancer. Current research also suggests vitamin C has a potential anticancer effect, particularly for cancer of the stomach, the rectum and the cervix. For vitamin E, epidemiological data give less conclusive results. Several prospective studies suggest the absence of any correlation between vitamin E intake and general risk of cancer. A Chinese trial has shown a decreased incidence of oesophageal and gastric carcinoma while a Finnish trial revealed increased incidence of cancer among smokers treated by beta-carotene and vitamin E. Selenium and zinc intake, based on geographical correlations, has also been suggested to affect cancer incidence, but the results of prospective studies are conflicting. For example in 10 such trials analyzing blood selenium levels and risk of cancer, 4 have demonstrated a significant correlation. Further research is needed but is hindered by the absence of an adequate animal model and the difficulty in conducting large clinical trials. Nevertheless, positive data collected to date must be validated to determine the real effect of dietary preventive measures in the fight against cancer.

Neoplasms

prevention & control

44621152

Guanidinium-grafted polyethylenimine: an efficient transfecting agent for mammalian cells.

Polyethylenimine (PEI) is one of the most efficient polycationic non-viral gene delivery vectors. Its efficiency and cytotoxicity depends on molecular weight, with the 25-kDa PEI being most efficient but accompanied with cytotoxicity. In the present study, enhancement in gene delivery efficiency along with reduction in cytotoxicity by attachment of guanidinium side group was explored. The hypothesis was that the guanidination would lead to the delocalization of charge present on primary amines of the polymer thereby leading to enhancement in gene delivery efficiency along with reduction in cytotoxicity. The polymer was guanidinated using O-methylisourea hemisulfate and the chemical linkage characterized by FTIR spectroscopy. The hydrodynamic diameter of guanidinated PEI-DNA complexes was determined using DLS. Subsequently, these complexes were used for DNA binding assay and zeta-potential measurements, taking native PEI as reference. Further, guanidinated PEI-DNA complexes were investigated for their gene delivery efficacy on HEK 293 cells. The hydrodynamic diameter of guanidinated PEI-DNA complexes was found to be in the range of 176-548 nm. As expected, the zeta potential values increased, on increasing the N/P ratios. It was found that guanidinated PEI had higher transfection efficiency at the majority of the N/P ratios tested as compared to commercially available transfecting agent lipofectin and native PEI itself. The toxicity of guanidinated PEI-DNA complexes was also reduced considerably in comparison to PEI polymer, as determined by MTT colorimetric assay. Out of the various derivatives prepared, gPEI 56% was found to be the most efficient in in vitro transfection.

DNA

administration & dosage

28080359

Pentadecapeptide BPC 157 cream improves burn-wound healing and attenuates burn-gastric lesions in mice.

The effects of the gastric pentadecapeptide BPC 157 were investigated when administered topically or systemically in burned mice. This agent is known to have a beneficial effect in a variety of models of gastrointestinal lesions, as well as on wound or fracture healing. Deep partial skin thickness burns (1.5x1.5 cm) covering 20% of total body area, were induced under anesthesia on the back of mice by controlled burning and gastric lesions were assessed 1, 2, 3, 7, 14 and 21 days following injury. The first application of BPC 157 was immediately following burning, and thereafter, once daily, until 24 h before sacrifice. In the initial experiments, exposure to direct flame for 5 s, the BPC 157 was applied at 10 microg or 10 ng/kg b.w. intraperitoneally (i.p.) by injection or alternatively, topically, at the burn, as a thin layer of cream (50 microg of BPC 157 dissolved in 2 ml of distilled water was mixed with 50 g of commercial neutral cream (also used as local vehicle-control)), while silver sulfadiazine 1% cream was a standard agent acting locally. Others received no local medication: they were treated i.p. by injection of distilled water (distilled water-control) or left without any medication (control). In subsequent experiments involving deeper burns (direct flame for 7 s), BPC 157 creams (50 microg, 5 microg, 500 ng, 50 ng or 5 ng of BPC 157 dissolved in 2 ml of distilled water was mixed with 50 g of commercial neutral cream), or vehicle as a thin layer of cream, were applied topically, at the burn. Compared with untreated controls, in both experiments, in the BPC 157 cream-treated mice all parameters of burn healing were improved throughout the experiment: less edema was observed and inflammatory cell numbers decreased. Less necrosis was seen with an increased number of capillaries along with an advanced formation of dermal reticulin and collagen fibers. An increased number of preserved follicles were observed. Two weeks after injury, BPC 157 cream-treated mice completely reversed the otherwise poor re-epithelization ratio noted in the untreated control or mice treated with vehicle only. Tensiometry investigation showed an increased breaking strength and relative elongation of burned skin, while water content in burned skin decreased. This was, however, not the case with the vehicle or silver sulfadiazine. Relative to the control values, in silver sulfadiazine cream-treated mice, only collagen fiber formation was increased, in addition to a decreased inflammatory cell number. Relative to control values, BPC 157 given i.p. decreased the number of inflammatory cells, lowered water content in burned skin, and raised breaking strength and relative elongation of burned skin during tensiometry. Through the experimental period, gastric lesions were continuously noted in all thermally injured mice left without local medication and they were consistently attenuated only by BPC 157 treatments: either given i.p. (at either dose), or given locally (at either concentration). Other treatments (i.e. local treatment with silver sulfadiazine cream or neutral cream in mice subjected for 5 s to direct flame), led to only poor, if any attenuation. This stable gastric pentadecapeptide appears to be active and gives a stimulation to burn healing at the defect site. The agent may act by causing an upregulation of the growth factors, as well as influencing other local factors.

Proteins

pharmacology

46105270

Exposure to HIV/AIDS information, AIDS knowledge, perceived risk and attitudes toward people with AIDS among primary school-children in northern Tanzania.

An AIDS survey based on WHO's KABP survey instrument for adolescents was implemented with sixth and seventh grade students attending one of 18 randomly selected primary schools in the Arusha and Kilimanjaro regions of Northern Tanzania (n = 2,026). While students reported having been exposed to several sources of AIDS information, overall knowledge level was low, particularly with respect to risk associated with causal contact, and the fact that a person can be infected and show no signs of the disease. Students who reported frequent exposure to AIDS information or who frequently talked to others about AIDS, were more knowledgeable regarding AIDS than students who reported less frequent exposure to AIDS information or communication. Furthermore, students with high scores on AIDS knowledge were more likely to report AIDS as a very severe disease. Also, they perceived themselves as less susceptible to AIDS, and were more likely to have a positive attitude toward spending time with and taking care of people with AIDS than did less knowledgeable students. It is recommended that primary schools be utilized as an arena for AIDS education in Tanzania.

HIV Infections

psychology

23882724

Evaluation of dogs with digit masses: 117 cases (1981-1991).

Medical records of 117 dogs with digit masses were reviewed. Of 124 digit masses, 76 (61%) were malignant neoplasms, 25 (20%) were benign neoplasms, and 23 (19%) were pyogranulomatous inflammation. Of 29 digits with radiographic evidence of bone lysis, 24 (83%) were affected by malignant masses, whereas only 5 of 29 (17%) digits with radiographic evidence of bone lysis were affected by benign or pyogranulomatous masses. Only 1 of 19 (5%) dogs with melanoma had radiographic evidence of lysis, but 20 of 25 (80%) dogs with squamous cell carcinoma had radiographic evidence of bone lysis. Thoracic radiographs of 95 dogs were available. Six of 19 (32%) dogs with melanoma had radiographic evidence of pulmonary metastasis at the time of diagnosis, whereas 3 of 24 (13%) dogs with squamous cell carcinoma had radiographic evidence of pulmonary metastasis at the time of diagnosis. Twenty-nine digit neoplasms were squamous cell carcinoma, and 19 of 29 (66%) arose from the subungual epithelium. Of 19 dogs with squamous cell carcinoma originating from the subungual epithelium, 18 (95%) survived for at least 1 year, whereas only 6 of 10 (60%) dogs with squamous cell carcinoma originating in other parts of the digit survived for at least 1 year. Furthermore, of 19 dogs with squamous cell carcinoma originating from the subungual epithelium, 14 (74%) survived at least 2 years, whereas only 4 of 9 (44%) dogs with squamous cell carcinoma originating in other parts of the digit survived for 2 years. Dogs with melanoma of the digits had a median survival time of 12 months, with 10 of 24 (42%) alive at 1 year and 3 of 23 (13%) alive at 2 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Squamous Cell

veterinary

32328409

Penicillin and vitamin A as possible therapeutic agents in pityriasis rubra pilaris

Pityriasis rubra pilaris (PRP) is a rare skin disorder with versatile clinical presentations. A 62‐year‐old Caucasian woman with progressive erythroderma and classic adult (type I) PRP is presented. Treatment with systemic steroids and methotrexate produced no improvement. Clinical remission was achieved after systemic therapy with penicillin (both intravenous and intramuscular) and vitamin A. The therapy of PRP is reviewed, focusing on a possible infectious genesis of PRP as well as the role of antibiotics in its management.

Anti-Bacterial Agents

administration & dosage

33776176

Neuronal control of airways smooth muscle.

Sensory afferent nerves relay impulses from the airways to the central nervous system so that appropriate changes in bronchomotor tone and breathing patterns may occur. The dominant efferent control of airways smooth muscle is exerted via bronchoconstrictor parasympathetic cholinergic nerves. In some species this is opposed by bronchodilator sympathetic noradrenergic nerves. In addition, there exist both excitatory bronchoconstrictor and inhibitory bronchodilator non-adrenergic, non-cholinergic pathways. This review examines the role of the different branches of the autonomic nervous system in the control of airways smooth muscle tone with particular reference to modulation of these branches and the interactions which may exist between them.

Neurons

physiology

19463670

Presence of human papillomavirus-18 and Epstein-Barr virus in a squamous cell carcinoma of the tongue in a 20-year-old patient. Case report and review of the current literature.

We report on a squamous cell carcinoma of the tongue in a 20-year-old woman with co-infection of the tumor with human papilloma virus type 18 and Epstein-Barr virus. To our knowledge, this is the first case of co-infection in carcinoma of the tongue to be reported. We review the present data and theories concerning viral oncogenesis of oral carcinomas.

Carcinoma, Squamous Cell

virology

861170

Survey on the impact of comorbid allergic rhinitis in patients with asthma

BackgroundAllergic rhinitis (AR) and asthma are inflammatory conditions of the airways that often occur concomitantly. This global survey was undertaken to understand patient perspectives regarding symptoms, treatments, and the impact on their well-being of comorbid AR and asthma.MethodsSurvey participants were adults with asthma (n = 813) and parents of children with asthma (n = 806) from four countries each in the Asia-Pacific region and Europe. Patients included in the survey also had self-reported, concomitant AR symptoms. Patients and parents were recruited by telephone interview or by direct interview.ResultsMost patients (73%) had pre-existing symptoms of AR when their asthma was first diagnosed. Shortness of breath (21%) was the most troublesome symptom for adults, and wheezing (17%) and coughing (17%) the most troublesome for children. Patients used different medications for treating asthma (most commonly short-acting β-agonists and inhaled corticosteroids) and for treating AR (most commonly oral antihistamines). The concomitant presence of AR and asthma disrupted the ability to get a good night's sleep (79%), to participate in leisure and sports activities (75%), to concentrate at work or school (69% of adults, 73% of children), and to enjoy social activities (57% of adults, 51% of children). Most patients (79%) reported worsening asthma symptoms when AR symptoms flared up. Many (56%) avoided the outdoors during the allergy season because of worsening asthma symptoms. Many (60%) indicated difficulty in effectively treating both conditions, and 72% were concerned about using excessive medication. In general, respondents from the Asia-Pacific region reported more disruption of activities caused by symptoms and more concerns and difficulties with medications than did those from Europe. Differences between the two regions in medication use included more common use of inhaled corticosteroids in Europe and more common use of Chinese herbal remedies in the Asia-Pacific region.ConclusionResults of this survey suggest that comorbid asthma and AR substantially impact patient well-being and that the worsening of AR symptoms in patients with asthma can be associated with worsening asthma symptoms. These findings underscore the need for physicians who treat patients with asthma to evaluate treatment options for improving symptoms of both AR and asthma when present concomitantly.

Asthma

epidemiology

92996376

StackSSSPred: A Stacking-Based Prediction of Supersecondary Structure from Sequence.

Supersecondary structure (SSS) refers to specific geometric arrangements of several secondary structure (SS) elements that are connected by loops. The SSS can provide useful information about the spatial structure and function of a protein. As such, the SSS is a bridge between the secondary structure and tertiary structure. In this chapter, we propose a stacking-based machine learning method for the prediction of two types of SSSs, namely, β-hairpins and β-α-β, from the protein sequence based on comprehensive feature encoding. To encode protein residues, we utilize key features such as solvent accessibility, conservation profile, half surface exposure, torsion angle fluctuation, disorder probabilities, and more. The usefulness of the proposed approach is assessed using a widely used threefold cross-validation technique. The obtained empirical result shows that the proposed approach is useful and prediction can be improved further.

Proteins

chemistry

23748445

Placebo substitution for methyldopa in geriatric hypertensive patients.

The aim of this study was to obtain an objective evaluation of the possibly inappropriate antihypertensive therapy of elderly patients; this was done by means of placebo substitution for methyldopa, one of the drugs taken by all the participating patients. Forty patients were recruited from a hospital outpatient clinic and randomly allocated to two groups. One group remained on treatment which included methyldopa, while a matching placebo tablet was substituted in the other group. The study was conducted over a period of 6 months in a single-blind manner. Methyldopa was reintroduced in the placebo group when one of the evaluation clauses was recorded. Only 2 patients in the placebo group required reintroduction of methyldopa tablets. In the rest of this group there was no significant difference between systolic and diastolic pressures before and after 6 months of placebo substitution. Withdrawal of unnecessary antihypertensive therapy in the elderly should be considered. Patients must be observed carefully and therapy reintroduced when blood pressures rise.

Hypertension

drug therapy

30232579

[Development of synaptic responses and membrane conductances of neurons of intracerebellar nuclei in the rat].

A study of synaptic responses and membrane conductances of intracerebellar nuclei neurones, from thick sagittal cerebellar slices maintained in vitro, has shown that 1) functional excitatory synapses are present on these neurones from birth, probably due to climbing and/or mossy fibre collaterals; 2) functional inhibitory synapses, due to monosynaptic projections of Purkinje cell axons onto intracerebellar nuclei, are present as early as postnatal day 2; 3) immature nuclear neurones display not only fast sodium conductances, but also slow calcium conductances which persist until weaning time together with fast sodium spikes.

Neurons

physiology

33295822

The Epstein-Barr virus and its association with human cancers.

The Epstein-Barr virus (EBV) has been linked to the development of a variety of human malignancies, including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma, some T cell lymphomas, post-transplant lymphoproliferative disease, and more recently, certain cancers of the stomach and smooth muscle. This review summarizes these associations and in particular the role of the viral latent genes in the transformation process.

Neoplasms

virology

19724745

Focal nodular hyperplasia of the liver associated with high-dosage estrogens.

A patient developed benign nodular hyperplasia of the liver after long-term, high-dose estrogen therapy. A 10.5-cm benign liver nodule appeared after three years of high-dose estrogen therapy and was resected. Fourteen months later, while still receiving estrogen, a 4.5-cm nodule and multiple small nodules were seen on angiography. Four months after estrogen was discontinued, the larger liver nodule disappeared and the smaller ones decreased.

Liver Neoplasms

chemically induced

16302741

Dual effects of neurokinin on calcium channel currents and signal pathways in neonatal rat nucleus tractus solitarius

Neurokinins, such as substance P (SP), modulate the reflex regulation of cardiovascular and respiratory function in the CNS, particularly in the nucleus tractus solitarius (NTS). There is considerable evidence of the action of SP in the NTS, but the precise effects have not yet been determined. Voltage-dependent Ca2+ channels (VDCCs) serve as crucial mediators of membrane excitability and Ca2+ -dependent functions such as neurotransmitter release, enzyme activity and gene expression. The purpose of this study was to investigate the effects of neurokinins on VDCCs currents (ICa) in the NTS using patch-clamp recording methods. In 142 of 282 neurons, an application of [Sar(9), Met(O(2)11]-substance P (SSP, NK(1) receptor agonist) caused facilitation of L-type I(Ba). Intracellular dialysis of the Galpha(q/11)-protein antibody attenuated the SSP-induced facilitation of I(Ba). In addition, phospholipase C (PLC) inhibitor, protein kinase C (PKC) inhibitor and PKC activator attenuated the SSP-induced the facilitation of I(Ba). In contrast, in 115 of 282 neurons, an application of SSP caused inhibition of N- and P/Q-types I(Ba). Intracellular dialysis of the Gbetagamma-protein antibody attenuated the SSP-induced inhibition of I(Ba). These results indicate that NK(1) receptor facilitates L-type VDCCs via Galpha(q/11)-protein involving PKC in NTS. On the other hand, NK(1) receptor inhibits N- and P/Q-types VDCCs via Galpha(q/11)-protein betagamma subunits in NTS.

Neurons

drug effects

206160730

PIOfix-study: effects of pioglitazone/metformin fixed combination in comparison with a combination of metformin with glimepiride on diabetic dyslipidemia.

OBJECTIVE Dyslipidemia in patients with type 2 diabetes is characterized by elevated triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol, and a predominance of small dense low-density lipoprotein (LDL) particles. Also, patients suffer from β-cell dysfunction, chronic systemic inflammation, increased hormonal visceral adipose tissue activity, and an increased risk of cardiovascular events. The aim of our study was to investigate the effect of a fixed pioglitazone + metformin (PM) combination (vs. glimepiride + metformin [GM]) on diabetic dyslipidemia. RESEARCH DESIGN AND METHODS A total of 288 type 2 diabetes patients completed this double-blind parallel study (187 men, 101 women; age [mean ± SD], 59 ± 10 years; body mass index, 32.6 ± 5.1 kg/m(2); hemoglobin A1c [HbA1c], 7.3 ± 0.8%). They were randomized to PM or GM for 6 months. Observation parameters at baseline and end point included HDL, LDL, triglycerides, fasting insulin, fasting glucose, total adiponectin, intact proinsulin, and high-sensitivity C-reactive peptide (hsCRP). RESULTS HDL increased in the PM group by 0.08 ± 0.25 mmol/L (GM, -0.01 ± 0.2.8 mmol/L; P < 0.001 vs. PM), whereas LDL increased in both groups (GM, 0.25 ± 0.90 mmol/L; PM, 0.29 ± 0.66 mmol/L; difference not significant between groups). Improvements were seen for triglycerides (PM, -0.47 ± 1.30; GM, -0.19 ± 1.39 mmol/L), HbA1c (PM, -0.8 ± 0.9%; GM, -1.0 ± 0.9%), and glucose (PM, -1.2 ± 2.1; GM, -1.2 ± 2.2 mmol/L). Decreases in fasting insulin (PM, -5.2 ± 11.9; GM, -0.1 ± 9.8 μU/mL; P < 0.001 between groups), hsCRP (PM, -0.9 ± 1.9; GM, 0.0 ± 1.8 mg/L; P < 0.001), and fasting intact proinsulin (PM, -5.5 ± 11.1; GM, -0.1 ± 10.0 pmol/L; P < 0.001) and an increase in adiponectin (PM, +6.8 ± 6.4 mg/L; GM, +0.7 ± 2.7 mg/L; P < 0.001) were seen in the PM arm, only. CONCLUSIONS With comparable glycemic control, the fixed PM combination was more efficacious on HDL cholesterol improvement than the GM combination. Additional positive effects were observed for biomarkers of lipid metabolism, β-cell function, activity of the visceral adipose tissue, and chronic systemic inflammation.

Diabetes Mellitus, Type 2

drug therapy

32856056

Quercus cerris extracts limit Staphylococcus aureus biofilm formation.

ETHNOPHARMACOLOGICAL RELEVANCE Quercus cerris L., Fagaceae has been used in traditional Mediterranean medicine for numerous purposes, including anti-infective therapies for diarrhea and wound care. AIM OF THE STUDY To evaluate the anti-staphylococcal activity of fractions of ethanolic extracts of Quercus cerris leaf and stem/fruit samples in models for biofilm and growth inhibition. MATERIALS AND METHODS Ethanolic extracts of Quercus cerris leaves and stems/fruits were prepared, resuspended in water and fractioned by successively partitioning with hexane, ethyl acetate and butanol. The ability of the fractions to inhibit Staphylococcus aureus biofilm formation was tested using static crystal violet staining methods and confocal laser scanning microscopy. Growth studies were conducted to determine if the diminished capacity to form a biofilm was related to growth inhibition. RESULTS The butanol extracts of both the leaf and stem/fruit samples were the most active, and at a dose of 200 μg/ml, the capacity to form a biofilm was limited to a level equivalent to that of the sarA mutant controls. Further examination of the impact of these fractions on Staphylococcus aureus growth revealed that biofilm inhibition by the leaf butanol fraction was due to its bacteriostatic activity. The stem/fruit butanol fraction, however, showed a limited impact on growth, thus demonstrating that biofilm inhibition in this case is not related to the bacteriostatic activity of the extract. CONCLUSION Our evaluation of a medicinal plant used in Mediterranean ethnotherapies for infectious disease has demonstrated significant activity in the inhibition of staphylococcal biofilm formation with a mechanism unrelated to staphylococcal growth inhibition. These results contribute towards validation of this botanical remedy and form the groundwork for future studies in the search for novel biofilm inhibiting drugs.

Anti-Bacterial Agents

pharmacology

932820

Body mass index and thoracic subcutaneous adipose tissue depth: possible implications for adequacy of chest compressions

ObjectiveAdequacy of cardiopulmonary resuscitation relies on compression of the thoracic cage to produce changes in intra-thoracic pressures sufficient to generate a pressure gradient. In order to evaluate the efficacy of cardiopulmonary resuscitation in morbid obesity, it is first necessary to determine the depth of thoracic subcutaneous adipose tissue (SAT) and to correlate this with body mass index (BMI).ResultsComputerised-tomography images of the thorax of 55 patients with a diagnosis of obesity or morbid obesity (mean BMI 45.95 kg/m2) were evaluated to determine the depth of SAT at the level at which chest compressions would be applied by a trained rescuer, and correlated with BMI. Mean anterior SAT was 36.53 mm, and mean posterior SAT was 50.73 mm. There was a significant correlation between BMI and anterior and posterior SAT for males (p < 0.05 for both), and females (p < 0.05 for both). The slope of the functions was considered sufficiently close to allow combining the data. This also showed a significant correlation between SAT and BMI (p < 0.01 for both). Both anterior and posterior SAT is correlated with BMI. This data allows development of a model to explore the efficacy of chest compressions in morbid obesity.

Obesity

diagnostic imaging

24808356

Formaldehyde inhalation during pregnancy abolishes the development of acute innate inflammation in offspring.

Formaldehyde (FA) is an environmental and occupational pollutant that induces programming mechanisms on the acquired immune host defense in offspring when exposed during the prenatal period. Hence, here we investigated whether the exposure of FA on pregnant rats could affect the development of an innate acute lung injury in offspring induced by lipopolissacaride (LPS) injection. Pregnant Wistar rats were exposed to FA (0.92 mg/m(3)) or vehicle (distillated water), both 1 h/day, 5 days/week, from 1 to 21 days of pregnancy. Non-manipulated rats were used as control. After 30 days of birth, the offspring was submitted to injection of LPS (Salmonella abortus equi, 5 mg/kg, i.p.). Systemic and lung inflammatory parameters were evaluated 24 h later. Exposure to FA during gestation abolished the development of acute lung injury in offspring, as observed by reduced number of leukocytes in the bronchoalveolar fluid (BAL), in the blood and in the bone marrow, and decreased myeloperoxidase activity in the lung. Moreover, phagocytes from BAL presented normal phagocytosis, but reduced oxidative burst. Alterations on the profile of inflammatory cytokines were evidenced by reduced mRNA levels of IL-6 and elevated levels of IL-10 and IFN gamma in the lung tissue. Indeed, mRNA levels of toll-likereceptor-4 and nuclear factor-kappa B translocation into the nucleus were also reduced. Additionally, hyperresponsiveness to methacholine was blunted in the trachea of offspring of FA exposed mothers. Together, our data clearly show that FA exposure in the prenatal period modifies the programming mechanisms of the innate defense in the offspring leading to impaired defense against infections.

Lung

drug effects

17662332

Pseudomonas mendocina native valve infective endocarditis: a case report

BackgroundGram-negative microorganisms are uncommon pathogens responsible for infective endocarditis. Pseudomonas mendocina, a Gram-negative water-borne and soil-borne bacterium, was first reported to cause human infection in 1992. Since then, it has rarely been reported as a human pathogen in the literature. We describe the first case of native valve infective endocarditis due to P. mendocina in the USA.Case presentationA 57-year-old white man presented with bilateral large leg ulcers, fever, and marked leukocytosis. His past medical history included gout and chronic alcohol use. P. mendocina was isolated from his blood cultures. A comprehensive review of P. mendocina infection in the literature was performed. A total of eight cases of P. mendocina infection were reported in the literature. More than two-thirds of the cases of P. mendocina septicemia were associated with native valve infective endocarditis. Thus, an echocardiogram was performed and demonstrated mitral valve endocarditis with mild mitral insufficiency. His leg wounds were debrided and were probably the source of P. mendocina bacteremia. Unlike Pseudomonas aeruginosa, P. mendocina is susceptible to third-generation cephalosporins. Our patient received a 6-week course of antimicrobial therapy with a favorable clinical outcome.ConclusionsOur reported case and literature review illuminates a rare bacterial cause of infective endocarditis secondary to P. mendocina pathogen. Native cardiac valves were affected in all reported cases of infective endocarditis, and a majority of affected heart valves were left-sided. The antibiotics active against P. mendocina are different from those that are active against P. aeruginosa, and they notably include third-generation cephalosporins. The outcome of all reported cases of P. mendocina was favorable and no mortality was described.

Anti-Bacterial Agents

administration & dosage

205675246

High–dose density chemotherapy followed by simple trachelectomy: full-term pregnancy

We report five patients with early-stage cervical cancer who do not fulfill criteria of fertility-sparing surgery (tumor more than 2 cm in the biggest diameter or infiltrating more than half of stroma). Five patients received three cycles of dose density neoadjuvant chemotherapy (NAC) at a 10-day interval: cisplatin plus ifosfamide in squamous cell cancer or plus doxorubicin in adenocarcinoma with good tolerance. After NAC, they underwent laparoscopic pelvic lymphadenectomy and vaginal simple trachelectomy. Two patients had no residual tumor, two had only microscopic residual disease, and one had macroscopic residual disease. Two women became pregnant 5 and 8 months after surgery, one delivered in term healthy baby and one is now in the second trimester of pregnancy without any complications. NAC followed by fertility-sparing surgery seems to be feasible treatment for women with tumor bigger than 2 cm or infiltrated more than half of the stroma.

Antineoplastic Agents

therapeutic use

205848453

Increased microstructural white matter correlations in left, but not right, temporal lobe epilepsy

Microstructural white matter tract correlations have been shown to reflect known patterns of phylogenetic development and functional specialization in healthy subjects. The aim of this study was to establish intertract correlations in a group of controls and to examine potential deviations from normality in temporal lobe epilepsy (TLE). We investigated intertract correlations in 28 healthy controls, 21 left TLE (LTLE) and 23 right TLE (RTLE). Nine tracts were investigated, comprising the parahippocampal fasciculi, the uncinate fasciculi, the arcuate fasciculi, the frontoparietal tracts, and the fornix. An abnormal increase in tract correlations was observed in LTLE, while RTLE showed intertract correlations similar to controls. In the control group, tract correlations increased with increasing fractional anisotropy (FA), while in the TLE groups tract correlations increased with decreasing FA. Cluster analyses revealed agglomeration of bilateral pairs of homologous tracts in healthy subjects, with such pairs separated in our LTLE and RTLE groups. Discriminant analyses aimed at distinguishing LTLE from RTLE, revealing that tract correlations produce higher rates of accurate group classification than FA values. Our results confirm and extend previous work by showing that LTLE compared to RTLE patients display not only more extensive losses in microstructural orientation but also more aberrant intertract correlations. Aberrant correlations may be related to pathologic processes (i.e., seizure spread) or to adaptive processes aimed at preserving key cognitive functions. Our data suggest that tract correlations may have predictive value in distinguishing LTLE from RTLE, potentially moving diffusion imaging to a place of greater prominence in clinical practice. Hum Brain Mapp, 36:85–98, 2015. © 2014 Wiley Periodicals, Inc.

Brain

pathology

218493003

Spectrum of false positive 18F-sodium fluoride (NaF) bone PET/CT findings in Oncology imaging; A narrative pictorial review of cases from a single institution.

Fluorine-18-sodium fluoride (18F-NaF) is a positron emission tomography (PET) bone imaging agent mainly used for oncology staging but may also be used in the evaluation of benign bone and joint pathology conditions. Fluorine-18-NaF is an excellent bone-seeking agent with high bone uptake owing to favorable biodistribution with rapid single-pass extraction, limited plasma protein binding and prompt renal clearance. Fluorine-18-NaF PET/computed tomography (CT) is highly sensitive in identifying both sclerotic and lytic bone metastatic lesions. Occasionally 18F-NaF uptake in benign bone lesions can mimic malignantpathology. In these cases, the pattern of 18F-NaF uptake may elicit a specific diagnosis and correlation with clinical information and morphological information from correlative CT is essential for a correct diagnosis. In the present article, we present a series of clinical cases demonstrating examples of 18F-NaF uptake in benign lesions which can simulate malignant pathology in patients undergoing cancer staging.

Neoplasms

diagnostic imaging

23852501

Use of Individual Differences Questionnaire with Psychiatric Inpatients

Paivio's Individual Differences Questionnaire was given to 47 psychiatric inpatients. Their mean verbal and imagery scores were higher than those for Paivio and Harshman's 713 students. Also, the latter had higher verbal than imagery scores, while the psychiatric group had the opposite. Subjects with affective disorders had significantly higher mean scores on a subscale which measures vividness of dreams, daydreams, and imagination than other diagnostic groups.

Mental Disorders

rehabilitation

15973298

NADPH Oxidase NOX5-S and Nuclear Factor κB1 Mediate Acid-Induced Microsomal Prostaglandin E Synthase-1 Expression in Barrett’s Esophageal Adenocarcinoma Cells

The mechanisms of progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma (EA) are not known. Cycloxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) has been shown to be important in esophageal tumorigenesis. We have shown that COX-2 mediates acid-induced PGE2 production. The prostaglandin E synthase (PGES) responsible for acid-induced PGE2 production in BE, however, is not known. We found that microsomal PGES1 (mPGES1), mPGES2, and cytosolic PGES (cPGES) were present in FLO EA cells. Pulsed acid treatment significantly increased mPGES1 mRNA and protein levels but had little or no effect on mPGES2 or cPGES mRNA. Knockdown of mPGES1 by mPGES1 small interfering RNA (siRNA) blocked acid-induced increase in PGE2 production and thymidine incorporation. Knockdown of NADPH oxidase, NOX5-S, a variant lacking calcium-binding domains, by NOX5 siRNA significantly inhibited acid-induced increase in mPGES1 expression, thymidine incorporation, and PGE2 production. Overexpression of NOX5-S significantly increased the luciferase activity in FLO cells transfected with a nuclear factor κB (NF-κB) in vivo activation reporter plasmid pNF-κB-Luc. Knockdown of NF-κB1 p50 by p50 siRNA significantly decreased acid-induced increase in mPGES1 expression, thymidine incorporation, and PGE2 production. Two novel NF-κB binding elements, GGAGTCTCCC and CGGGACACCC, were identified in the mPGES1 gene promoter. We conclude that mPGES1 mediates acid-induced increase in PGE2 production and cell proliferation. Acid-induced mPGES1 expression depends on activation of NOX5-S and NF-κB1 p50. Microsomal PGES1 may be a potential target to prevent or treat EA.

Adenocarcinoma

metabolism

3102933

[Viridans streptococci in human infections: identification and susceptibility to antibiotics].

A method for the speciation of viridans streptococci (devoided of group antigens) is described. The major identification criteria are based on the reaction of a series of biochemical tests such as acid production in lactose, inuline, raffinose, mannitol and sorbitol, hydrolysis of arginine, esculin and Na hippurate, and production of polysaccharides in 5% sucrose media. A total of 460 strains were isolated from human specimens and identified as follows: 118 Streptococcus mitis, 102 S. sanguis II, 75 S. Sanguis I, 87 S. milleri (Streptococcus MG-intermedius), 28 S. mutans, 25 S. salivarius, 14 S. morbillorium, 2 S. uberis and 9 unspeciated. Susceptibility to antibiotics was studied for 318 strains: 63% of them were susceptible to all drugs tested; 37% of the strains were resistant to one or several antibiotics as follows: 34% to tetracycline, 8.5% to macrolides and related drugs, 5.3% to streptomycin and/or kanamycin (MIC greater than 2,000 micrograms/ml), 5% to penicillin (MIC = 1-4 micrograms/ml) and 4% to chloramphenicol.

Anti-Bacterial Agents

pharmacology

25489945

Transcatheter arterial chemoembolization for hepatocellular carcinoma fed by the reconstructed inferior phrenic artery: anatomical and technical analysis.

PURPOSE To evaluate reconstructed patterns of occluded inferior phrenic artery (IPA) and determine the technical success rate and complications of transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) fed by the occluded IPA through the anastomosing branch. MATERIALS AND METHODS In 19 patients, 24 IPAs, including two that had been previously embolized, were demonstrated through collateral pathways. The incidence of each collateral circulation was evaluated. Thirteen IPAs in 12 patients fed the tumor and TACE was attempted. TACE was performed only if the catheter could be advanced into the anastomosing branch so that the nontarget branches were avoided. RESULTS A reconstructed unilateral IPA was observed in 14 patients (11 right IPAs and three left IPAs) and two reconstructed IPAs were observed in five. The IPA was demonstrated through the dorsal pancreatic artery (n = 13), inferior or middle adrenal artery (n = 7), left gastric artery (n = 2), contralateral IPA (n = 2), lumbar artery (n = 1), and small branch derived from the celiac trunk (n = 1). Five IPAs (21%) were demonstrated through more than two separate arteries, including two demonstrated through both dorsal pancreatic arteries arising from the celiac and superior mesenteric artery. The IPA opacified through the lumbar artery had been previously embolized. TACE of the reconstructed IPA was possible in 10 of 13 IPAs (77%). Complications related to the procedure were a small amount of pleural effusion (n = 4) and basal atelectasis (n = 2). CONCLUSION The IPA is reconstructed mainly through the retroperitoneal anastomosing branch in the upper abdomen. TACE of the reconstructed IPA can be performed with a high success rate without major complications.

Liver Neoplasms

therapy

21732184

Creatinine-based glomerular filtration rate estimation in patients with liver disease: the new Chronic Kidney Disease Epidemiology Collaboration equation is not better

Objectives Limitations of serum creatinine in patients with an impaired liver function are well known. The commonly used modification of diet in renal disease (MDRD) equation has a low diagnostic performance to approximate kidney function in patients after liver transplantation (LT) and patients with liver cirrhosis (LC). The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula has been shown to provide a more accurate estimation of kidney function in patients with chronic kidney disease, but studies in patients with liver disease are lacking. Methods We evaluated the diagnostic performance of CKD-EPI in comparison with the re-expressed MDRD formula in patients after LT (group 1; n=59) and in patients suffering from LC (group 2; n=44). GFR was measured by 99mTc-diethylenetriamine penta-acetic acid (group 1) and inulin clearance (group 2). Bias, precision, and accuracy as compared with the measured GFR were determined. Results The measured mean GFR (95% confidence interval) was 52.3 ml/min/1.73 m2 (47.7; 56.9; group 1) and 35.3 ml/min/1.73 m2 (29.12; 41.3; group 2), respectively. In transplanted patients GFR estimation by CKD-EPI and MDRD did not significantly differ with respect to bias (9.7 vs. 4.3 ml/min/1.73 m2), precision (16.9 vs. 15.5 ml/min/1.73 m2) and accuracy (64.4 vs. 69.5% within 30% of ‘true GFR’). In patients with LC, both formulae showed a very high bias (42.5 vs. 40.1 ml/min/1.73 m2), a very low precision (20.7 vs. 25.7 ml/min/1.73 m2) and accuracy (6.8 within 30% of the measured GFR in both groups). Conclusion The CKD-EPI equation does not improve the creatinine-based GFR estimation in patients after LT. In patients with LC, both equations should not be applied as they extremely overestimate GFR.

Kidney

physiopathology

207740250

Functional Characteristics of Reversibly Immortalized Hepatic Progenitor Cells Derived from Mouse Embryonic Liver

Background/Aims: Liver is a vital organ and retains its regeneration capability throughout adulthood, which requires contributions from different cell populations, including liver precursors and intrahepatic stem cells. To overcome the mortality of hepatic progenitors (iHPs) in vitro, we aim to establish reversibly immortalized hepatic progenitor cells from mouse embryonic liver. Methods and Results: Using retroviral system to stably express SV40 T antigen flanked with Cre/LoxP sites, we establish a repertoire of iHP clones with varied differentiation potential. The iHP cells maintain long-term proliferative activity and express varied levels of progenitor markers (Pou5f1/Oct4 and Dlk) and hepatocyte markers (AFP, Alb and ApoB). Five representative iHP clones express hepatic/pancreatic transcription factors HNF3α/Foxa1, HNF3β/Foxa2, and HNF4α/MODY1. Dexamethasone is shown to promote the expression of hepatocyte markers AFP and TAT, along with ICG-uptake and glycogen storage functions in the iHP clones. Cre-mediated removal of SV40 T antigen reverses the proliferative activity of iHP cells. When iHP cells are subcutaneously implanted in athymic nude mice, no tumor formation is observed for up to 8 weeks. Conclusions: We demonstrate that the established iHP cells are stable, reversible, and non-tumorigenic hepatic progenitor-like cells, which should be valuable for studying liver organogenesis, metabolic regulations, and hepatic lineage-specific differentiation.

Liver

physiology

18384225

Progressive muscle relaxation reduces migraine frequency and normalizes amplitudes of contingent negative variation (CNV)

BackgroundCentral information processing, visible in evoked potentials like the contingent negative variation (CNV) is altered in migraine patients who exhibit higher CNV amplitudes and a reduced habituation. Both characteristics were shown to be normalized under different prophylactic migraine treatment options whereas Progressive Muscle Relaxation (PMR) has not yet been examined. We investigated the effect of PMR on clinical course and CNV in migraineurs in a quasi-randomized, controlled trial.MethodsThirty-five migraine patients and 46 healthy controls were examined. Sixteen migraineurs and 21 healthy participants conducted a 6-week PMR-training with CNV-measures before and after as well as three months after PMR-training completion. The remaining participants served as controls. The clinical course was analyzed with two-way analyses of variance (ANOVA) with repeated measures. Pre-treatment CNV differences between migraine patients and healthy controls were examined with t-tests for independent measures. The course of the CNV-parameters was examined with three-way ANOVAs with repeated measures.ResultsAfter PMR-training, migraine patients showed a significant reduction of migraine frequency. Preliminary to the PMR-training, migraine patients exhibited higher amplitudes in the early component of the CNV (iCNV) and the overall CNV (oCNV) than healthy controls, but no differences regarding habituation. After completion of the PMR-training, migraineurs showed a normalization of the iCNV amplitude, but neither of the oCNV nor of the habituation coefficient.ConclusionsThe results confirm clinical efficacy of PMR for migraine prophylaxis. The pre-treatment measure confirms altered cortical information processing in migraine patients. Regarding the changes in the iCNV after PMR-training, central nervous mechanisms of the PMR-effect are supposed which may be mediated by the serotonin metabolism.

Brain

physiopathology

3006380

Unique Features of Germline Variation in Five Egyptian Familial Breast Cancer Families Revealed by Exome Sequencing

Genetic predisposition increases the risk of familial breast cancer. Recent studies indicate that genetic predisposition for familial breast cancer can be ethnic-specific. However, current knowledge of genetic predisposition for the disease is predominantly derived from Western populations. Using this existing information as the sole reference to judge the predisposition in non-Western populations is not adequate and can potentially lead to misdiagnosis. Efforts are required to collect genetic predisposition from non-Western populations. The Egyptian population has high genetic variations in reflecting its divergent ethnic origins, and incident rate of familial breast cancer in Egypt is also higher than the rate in many other populations. Using whole exome sequencing, we investigated genetic predisposition in five Egyptian familial breast cancer families. No pathogenic variants in BRCA1, BRCA2 and other classical breast cancer-predisposition genes were present in these five families. Comparison of the genetic variants with those in Caucasian familial breast cancer showed that variants in the Egyptian families were more variable and heterogeneous than the variants in Caucasian families. Multiple damaging variants in genes of different functional categories were identified either in a single family or shared between families. Our study demonstrates that genetic predisposition in Egyptian breast cancer families may differ from those in other disease populations, and supports a comprehensive screening of local disease families to determine the genetic predisposition in Egyptian familial breast cancer.

Breast Neoplasms

genetics

13451469

Hydrophilic acrylic intraocular lens (Akreos AO MI60) optic opacification in patients with diabetic retinopathy

Recently, the approval of the hydrophilic acrylic intraocular lens (IOL; Akreos AO MI60; Bausch & Lomb, Rochester, New York) made microcoaxial surgery possible through a sub-2 mm incision. Although hydrophilic acrylic IOLs have proven to be highly biocompatible,1 several studies reported a late opacification of IOLs due to calcium deposits.2 3 The authors report five patients with calcium deposits on the anterior surface of Akreos AO MI60 IOLs which occurred after phacoemulsification and 23-gauge transconjunctival sutureless vitrectomy (TSV) for diabetic vitreous haemorrhage (VH). To our knowledge, opacification for this IOL design has not been reported before. One of the authors (SYK) implanted the Akreos AO MI60 IOLs in 208 cases between November 2008 and December 2009. Eighty-nine cases had phacoemulsification and 23-gauge TSV for diabetic VH. The authors observed five patients (2.4%) with IOL opacification from the 208 cases. Clinical characteristics of the five patients who had IOL opacification are shown in table 1 …

Diabetes Mellitus, Type 2

complications

33607672

Cost analysis of aggressive breast cancer screening.

It is estimated that mammographic and physical examination (PE) screening would cost $3,866 per person year gained; screening with PE alone would cost $4,550. Sixty thousand person years are gained with combined screening, and 24,000 with PE alone per million women screened. The cost per cancer found is $9,046; for each highly curable cancer $26,961, and for each death averted $61,100. An estimated 16 years are added to each life saved. The cost per patient screening examination, using all techniques, is $20.04.

Breast Neoplasms

epidemiology

19947633

Salvage for nail breakage in femoral intramedullary nailing.

Proximal fractures of femur represent an important cause of hospitalization, morbidity and mortality for elderly patients. Femoral intramedullary nailing is an option to achieve a stable osteosynthesis but the breakage is a rare complication. The aim was to determinate the prevalence, causes, management and functional outcomes of this patients in our hands. Retrospective review of 1246 proximal femur fractures operated between 2003 and 2012. We analyse epidemiological data, fracture type and the quality of closed reduction and fixation by preoperative and postoperative radiology. Type of salvage procedure chosen for each case is presented. Functional outcome and quality of life questionnaire was obtained by Barthel index and Short Form 12 version 2. 11 cases (0.88%) were identified. The type of initial fracture was 7 cases AO/OTA 31A3 and 4 cases AO/OTA 31A2. The implant failure was detected at 11 months after surgery (SD 6.39). Nail breakage occurred in three different points: 7 cases in the proximal aperture, 3 cases in cervicocephalic screw and 1 case in the distal aperture of the nail. The association of nonunion at fracture site and progressive hip pain was observed in all cases. Different salvage procedures were performed: 7 cases osteosynthesis revision (nail or dynamic condilar screw plate), 2 cases arthroplasty and 2 cases conservative treatment. The main Barthel score before the salvage procedure was 63.2 (SD 13). At final follow-up, this score improved to 72.8 (SD 20.38). To the best of our knowledge, this study represents the largest series of cases of trochanteric nail breakage due to material fatigue. This complication is rare (0.88%) that can foresee in unstable fractures with delayed union. The type of salvage should be individualized showing acceptable functional outcome in our series.

Postoperative Complications

surgery

15544773

Improving mental health care transitions for children and youth: a protocol to implement and evaluate an emergency department clinical pathway

BackgroundWhile the emergency department (ED) is often a first point of entry for children and youth with mental health (MH) concerns, there is a limited capacity to respond to MH needs in this setting. Child MH systems are typically fragmented among multiple ministries, organizations, and providers. Communication among these groups is often poor, resulting in gaps, particularly in transitions of care, for this vulnerable population. The evidence-based Emergency Department Mental Health Clinical Pathway (EDMHCP) was created with two main goals: (1) to guide risk assessment and disposition decision-making for children and youth presenting to the ED with MH concerns and (2) to provide a streamlined transition to follow-up services with community MH agencies (CMHAs) and other providers. The purpose of this paper is to describe our study protocol to implement and evaluate the EDMHCP.Methods/designThis mixed methods health services research project will involve implementation and evaluation of the EDMHCP in four exemplar ED-CMHA dyads. The Theoretical Domains Framework will be used to develop a tailored intervention strategy to implement the EDMHCP. A multiple baseline study design and interrupted time-series analysis will be used to determine if the EDMHCP has improved health care utilization, medical management of the MH problems, and health sector coordination. The primary process outcome will be the proportion of patients with MH-specific recommendations documented in the health record. The primary service outcome will be the proportion of patients receiving the EDMHCP-recommended follow-up at 24-h or at 7 days. Data sources will include qualitative interviews, health record audits, administrative databases, and patient surveys. A concurrent process evaluation will be conducted to assess the degree of variability and fidelity in implementation across the sites.DiscussionThis paper presents a novel model for measuring the effects of the EDMHCP. Our development process will identify how the EDMHCP is best implemented among partner organizations to deliver evidence-based risk management of children and youth presenting with MH concerns. More broadly, it will contribute to the body of evidence supporting clinical pathway implementation within novel partnerships.Trial registrationClinicalTrials.gov (NCT02590302)

Mental Disorders

therapy

33140288

Helical tomotherapy and intensity modulated proton therapy in the treatment of dominant intraprostatic lesion: a treament planning comparison.

PURPOSE To compare helical tomotherapy (HT) and intensity modulated proton therapy (IMPT) for prostate cancer irradiation while concomitantly boosting dominant intraprostatic lesions (DILs). METHODS AND MATERIALS Treatment plans of seven patients were designed for HT and IMPT (pencil beam size: 3mm sigma). The prescribed median PTV/DIL doses were 71.4/100 Gy in 28 fractions, while satisfying "safe" dose constraints for organs at risks (OARs) including rectum, bladder, femoral heads, penile bulb and urethra. The planner could further reduce the dose to OARs if PTV/DIL constraints were reached. RESULTS IMPT achieved better dose conformity (CI=1.11 vs 1.31, p<0.05) and coverage (V95%=97.3% vs 95.3%, p<0.05) in PTV. Concerning DIL volumes, both techniques delivered the prescribed dose (D median: HT=100 Gy, IMPT=102.1 Gy) with similar dose conformity (CI: HT=1.49, IMPT=1.44) and same dose homogeneity, D99%, D1%, while satisfying the OARs constraints. Excepting urethra, the sparing of OARs was significantly better with IMPT; in general, the lower the dose, the greater the benefit of IMPT. Normal tissue complication probabilities for the rectum were in favor of IMPT with an absolute reduction of 3-8%, depending on the NTCP model (p<0.05). CONCLUSIONS Both techniques allowed delivering 100 Gy to DILs, while complying with the OARs constraints. IMPT was superior in sparing OARs for doses up to approximately 70 Gy, with larger benefit at lower doses.

Prostatic Neoplasms

radiotherapy

23686914

Local recurrence after surgery for early stage lung cancer

The objective of the current study was to evaluate the actuarial risk of local failure (LF) after surgery for stage I to II nonsmall cell lung cancer (NSCLC) and assess surgical and pathologic factors affecting this risk.

Lung Neoplasms

pathology

52055759

Cationic cholesterol derivative efficiently delivers the genes: in silico and in vitro studies

The aims of the research work were to synthesize ethyl(cholesteryl carbamoyl)-l-arginate (ECCA), an arginine-conjugated cholesterol derivative, and to evaluate its application as a gene delivery vector. The interactions of ECCA with DNA duplex were studied using molecular dynamics (MD) simulations. It was found that the guanidine group of ECCA could interact with the phosphate group of DNA through ionic interactions as well as hydrogen bonds. The structure of DNA was stable throughout the simulation time. Liposomes were formulated using ECCA and soya phosphatidylcholine (SPC) by a thin-film hydration method. They had the particle size of ~ 150 nm and the zeta potential of + 51 mV. To ensure the efficient binding of DNA to the liposomes, the ratio of DNA to ECCA was optimized using gel retardation assay. Further, serum stability, haemolysis and cytotoxicity studies were carried out to determine the stability and safety of the lipoplexes. Circular dichroism spectroscopy was used to determine the interaction of DNA and cationic liposomes. Cellular uptake pathway was determined by studying the uptake of coumarin-loaded lipoplexes at 4 °C and in the presence of uptake inhibitors, i.e. genistein, chlorpromazine and methyl-β-cyclodextrin. Transfection studies were carried out to evaluate the transfection efficacy of the ECCA-loaded lipoplexes. The binding of DNA and lipoplexes was found to be stable in the presence of serum, and no degradation of DNA was observed. The lipoplexes showed low haemolysis and cytotoxicity. The uptake of coumarin-loaded liposomes was decreased up to ~ 20% in the presence of clathrin- and caveola-mediated uptake inhibitors, indicating a role of both the pathways in the uptake of the inhibitors. Satisfactory transfection efficiency was obtained compared to Lipofectamine®. Thus, cationic cholesterol derivative is a useful tool for gene delivery vector.

DNA

chemistry

5708056

Constitutive and allergen-induced expression of eotaxin mRNA in the guinea pig lung

Eotaxin is a member of the C-C family of chemokines and is related during antigen challenge in a guinea pig model of allergic airway inflammation (asthma). Consistent with its putative role in eosinophilic inflammation, eotaxin induces the selective infiltration of eosinophils when injected into the lung and skin. Using a guinea pig lung cDNA library, we have cloned full-length eotaxin cDNA. The cDNA encodes a protein of 96 amino acids, including a putative 23-amino acid hydrophobic leader sequence, followed by 73 amino acids composing the mature active eotaxin protein. The protein-coding region of this cDNA is 73, 71, 50, and 48% identical in nucleic acid sequence to those of human macrophage chemoattractant protein (MCP) 3, MCP-1, macrophage inflammatory protein (MIP) 1 alpha, and RANTES, respectively. Analysis of genomic DNA suggested that there is a single eotaxin gene in guinea pig which is apparently conserved in mice. High constitutive levels of eotaxin mRNA expression were observed in the lung, while the intestines, stomach, spleen, liver, heart, thymus, testes, and kidney expressed lower levels. To determine if eotaxin mRNA levels are elevated during allergen-induced eosinophilic airway inflammation, ovalbumin (OVA)-sensitized guinea pigs were challenged with aerosolized antigen. Compared with the lungs from saline-challenged animals, eotaxin mRNA levels increased sixfold within 3 h and returned to baseline by 6 h. Thus, eotaxin mRNA levels are increased in response to allergen challenge during the late phase response. The identification of constitutive eotaxin mRNA expression in multiple tissues suggests that in addition to regulating airway eosinophilia, eotaxin is likely to be involved in eosinophil recruitment into other tissues as well as in baseline tissue homing.

Lung

metabolism

73490406

Recent advances in the management of hepatocellular carcinoma: First, cut … is the deepest or is it “no‐touch” and exercise?

Remarkable advances have been made in the curative management of hepatocellular carcinoma (HCC) in the past decade, particularly by surgical means, with the continuing refinement of intraoperative instruments and technique, perioperative care as well as the indisputable success of liver transplantation in individuals with end stage liver disease. The literature is populated by studies in afflicted patients who are fortunate enough to access tertiary-level, city-based health services that can offer such sophisticated and financially costly interventions. However, a relative paucity of data remains in the reporting of the inequity of access to HCC treatment opportunities and its impact on patient outcomes. In this issue of JGH, Sobotka et al. report on geographic differences in HCC treatment in the United States of America (USA). The authors performed a retrospective analysis of over 62 000 patients with HCC and their management using the Nationwide Inpatient Sample (NIS) database, spanning 2010–2013. NIS is one of the USA’s largest publicly available data repositories of information drawing from over 7 million hospital annual discharges from across the nation. Does geography play a role in how patients with HCC in the USA are treated? In short, it used to be, but no longer so, by virtue of similar rates of hepatic resection, ablation, or transarterial chemoembolization (TACE), regardless of which region of the USA patients hail from. However, when it came to the issue of access to liver transplantation, “some are more equal than others.” The rate of liver transplantation for HCC had assumed parity in all regions of the USA by 2013 but remained significantly lower for patients who lived in the West, especially when compared to the Midwest. The tyranny of distance was attributed as a possible contributing factor, with those living further away from a transplant center being less likely to receive a liver transplant. Interestingly, this study also showed that the West had the highest percentage of patients of Asian, Pacific Islander, and Hispanic backgrounds than any other regions of the USA reviewed. While Sobotka et al. note geographical disparities to access of care for HCC in North America are improving, it is cold cause for comfort when we reflect on the Asia Pacific experience where the burden of HCC has been a harsh reality for at least two decades. Factor into the equation, limited centers for liver transplantation, a shortage of donor organs and in many countries, lack of universal access to tertiary level, specialist hepatology care and screening, the diagnosis of HCC in cirrhotic individuals is made too often, too late for curative management. It has been said that “necessity is the mother of invention.” In Japan, this old adage rings true in innovations made in the active palliative management of HCC. Classical monopolar percutaneous radiofrequency ablation (RFA) is used in the treatment and/or palliation of HCC and involves the generation of an electric current through a monopolar electrode tip inserted into a small HCC (usually less than 5 cm). This approach induces ionic agitation and heat (up to 100°C) thereby leading to coagulative necrosis of local and surrounding tumor cells/tissue. This heat propagates in a centrifugal direction, from the center of the tumor to its periphery so not surprisingly, the efficacy of “tumor kill” falls with increasing distance from the electrode. This kill effect drops off further if neoplastic tissue is located close to a major blood vessel (“heat sink effect” of adjacent blood flow). In recent attempts to optimize the size and efficacy of RFA, new ablation equipment have been devised. One such development is that of multipolar RFA with the added refinement of “no-touch” requiring no direct puncture of the tumor for ablation. Hirooka et al. from Ehime, Japan, report their experience with “no-touch” RFA in preventing intra-hepatic metastasis of HCC, in a prospective cohort study of 231 patients in the current issue of JGH. “No-touch” ablation was performed in HCCs varying in size from 12 to 23 mm, with 2 or 3 internally cooled bipolar electrodes placed simultaneously around a tumor focus and RFA deployed using high frequency power output (60 W) controlled by an automated resistance-controlled system. The rate of complete radiological necrosis was 100% in both monopolar direct puncture RFA and “no-touch” multipolar RFA groups. Cumulative intra-subsegmental tumor recurrence-free survival rates were significantly higher with “no-touch” compared with direct puncture ablation. Complications were few and transient. There were no deaths in either group treated. Limitations acknowledged, the findings of this study are encouraging and provide novel opportunities for larger randomized controlled RFA trials in early and advanced HCC to be conducted prospectively over a longer duration. “Weak, wan and wasted” has been used to describe many of Charles Dickens’ characters in Victorian England where socioeconomic inequities blighted many of the “common” people; these descriptors could just as appropriately be applied to patients with cirrhosis or cancer. The term “sarcopenia” was first coined by Irwin Rosenberg in 1989 and is derived from the Greek words, “sarx” and “penia” meaning “flesh/muscle” and “loss,” respectively. Primary sarcopenia, or age-related sarcopenia, may begin as early as the 4th decade of life, is progressive, and can result in up to 50% loss of skeletal muscle mass by the 8th decade of life. Sarcopenia caused by chronic conditions, such as cirrhosis or malignancy, is referred to as secondary sarcopenia. Sarcopenia itself is an independent predictor of poor survival in cirrhotic patients with or without HCC and is associated with increased cost of treatment and length of stay in hospital, as well as preand posttransplant mortality. TACE is a treatment option for patients with advanced HCC and may be complicated by fever, post-embolization syndrome and transient hepatic insufficiency. Further, patients subjected to TACE are not infrequently instructed to rest for extended periods doi:10.1111/jgh.14632

Liver Neoplasms

therapy

37823108

Chronic lymphocytic leukemia involving the coronary arteries with accompanying acute myocardial infarction.

An 83-year-old man with chronic lymphocytic leukemia (CLL) for 10 years presented with dyspnea and hypotension. Blood investigations and electrocardiogram were consistent with acute myocardial infarction. The patient deteriorated quickly and died shortly thereafter. At autopsy, there was severe atherosclerosis of the coronary arteries and an inferolateral left ventricular wall myocardial infarct. Microscopy showed that CLL involved the nodes, liver, spleen, bowel, and kidneys. The coronary artery walls were infiltrated with leukemia cells invading the tunica media and the atheromatous plaque. Infiltration of the coronary arteries by CLL is not common and the possible role in coronary syndromes is discussed.

Myocardial Infarction

etiology

23617012

Levels of leptin during hydrocortisone infusions that mimic normal and reversed diurnal cortisol levels in subjects with adrenal insufficiency.

Levels of leptin throughout the day follow a circadian pattern, with a trough in the late morning/early afternoon and a peak at midnight. This pattern of appearance of leptin correlates inversely with the circadian appearance of cortisol. Pharmacological doses of cortisol increase leptin messenger RNA expression in vitro and raise plasma leptin levels in animals and humans. To determine whether the circadian appearance of leptin might be accounted for by delayed effects from physiological cortisol secretion on fat cells, seven subjects with confirmed adrenal failure were admitted to the Clinical Research Center, on three separate dates, to receive 48-h infusions of: continuous normal saline (NS), a normal daily amount and diurnal pattern of cortisol (ND), and a normal daily amount but reversed diurnal pattern of cortisol. Blood samples were taken every 15 min during the second 24 h of infusion and pooled for hourly measurements of leptin. The circadian pattern of leptin appearance was unchanged during all of the infusion protocols. Area-under-the-curve analysis showed no differences in the total amount of leptin during the NS and ND protocols (20,565 ng/mL x 24 h vs. 20,637 ng/mL x 24 h during NS and ND protocols, respectively; P = 0.94). Acute changes in physiological levels of cortisol do not affect the circadian appearance of leptin in subjects with adrenal failure, nor is cortisol required to maintain normal leptin levels for up to 72 h. The circadian variation of leptin levels cannot be accounted for by normal activity of the hypothalamic-pituitary-adrenal axis.

Proteins

metabolism

3927495

Multiple Short Bouts of Walking Activity Attenuate Glucose Response in Obese Women.

BACKGROUND We sought to determine the effect of multiple walking breaks from sedentary behavior (SED) on glucose responses in sedentary obese women. MATERIALS AND METHODS Ten women [aged = 36 (5) y, body mass index = 38.0 (1.6) kg/m2, body fat = 49.6 (1.4)%] completed 3 conditions (48-h "washout" in-between conditions) following a standardized meal in random order: 4-hour SED, 4-hour SED with 2 minutes of moderate-intensity walking every 30 minutes (SED + 2 min), and 4-hour SED with 5 minutes of moderate-intensity walking every 30 minutes (SED + 5 min). Measurements included continuous interstitial glucose concentration monitoring immediately before and during standardized conditions and accelerometry for physical activity patterns during and in-between the standardized conditions. Repeated-measures 1-way analyses of variance (α = .05) with Bonferroni correction for post hoc comparisons were performed. Effect sizes (d [95% confidence interval]) were calculated as mean difference from SED/pooled standard deviation. RESULTS Sedentary time was similar in the 48 hours preceding each condition (P > .05). By design, sedentary time was different between conditions (P < .001). Compared with SED, 2-hour postprandial glucose positive incremental area under the curve was lower for SED + 5 minutes (P = .005; d = - 0.57 [-1.48, 0.40]), but not for SED + 2 minutes (P = .086; d = - 0.71 [-1.63, 0.27]). Four-hour postprandial glucose area under the curve was similar between conditions (P > .05). CONCLUSION In sedentary obese women, 5 minutes of moderate-intensity walking breaks from SED each 30 minutes attenuate 2-hour postprandial glucose excursions.

Obesity

therapy

147642

Role of calcium influx in cytotoxic T lymphocyte lytic granule exocytosis during target cell killing.

One mechanism cytotoxic T lymphocytes use to kill targets is exocytosis of cytotoxic agents from lytic granules, a process that requires Ca(2+) influx. We investigated the role of Ca(2+) influx in granule exocytosis using TALL-104 human leukemic cytotoxic T cells triggered via a bispecific antibody containing an anti-CD3 F(ab') to kill Raji B lymphoma cells. Using a novel fluorescence method, we detected target-directed release of approximately 15% of lytic granules during killing. Consistent with previous work, we observed sustained CTL Ca(2+) gradients during killing, but gradients reflect the behavior of Fura-2 in granules. Rapid imaging experiments suggest that Ca(2+) channels are not polarized during killing, indicating that Ca(2+) influx does not direct granule reorientation. Furthermore, we find that Ca(2+) acts via a high-affinity interaction to promote granule exocytosis.

Calcium

immunology

19127307

The early kinetics of gentamicin uptake into the inner ear.

Transtympanic gentamicin administration has become a popular modality in the treatment of Ménière's disease. This modality and other inner-ear medical therapy are gaining increased clinical and scientific attention. We previously described the kinetics and effects of gentamicin uptake into the inner ear after delivery of the medicine into the middle ear using a variety of different techniques and sustained-release modalities [1]. In our previous work, we reported an early peak perilymph concentration and the presence of intracellular gentamicin at the 4-hour time point. We also demonstrated the activation of inner-ear damage pathways at this early time point. In this report, we examine the kinetics of gentamicin at very early time points, 1 and 2 hours after administration. Healthy adult chinchillas underwent implantation of middle-ear sustained-release devices (one to each ear) containing gentamicin. The animals then were maintained in a neutral position and underwent perilymph gentamicin sampling at the two predetermined time points. This technique allowed us to assess accurately very early time point inner-ear gentamicin kinetics and to compare the activity. The samples then were run for concentration using mass spectrometry. The information gained from this study may increase our scientific understanding about the effects of gentamicin on the inner ear and may allow clinicians to treat patients more effectively for inner-ear disorders.

Anti-Bacterial Agents

pharmacokinetics

214781293

Effect of xenon and dexmedetomidine as adjuncts for general anesthesia on postoperative emergence delirium after elective cardiac catheterization in children: study protocol for a randomized, controlled, pilot trial

Background Emergence delirium, a manifestation of acute postoperative brain dysfunction, is frequently observed after pediatric anesthesia and has been associated with the use of sevoflurane. Both xenon and dexmedetomidine possess numerous desirable properties for the anesthesia of children with congenital heart disease, including hemodynamic stability, lack of neurotoxicity, and a reduced incidence of emergence delirium. Combining both drugs has never been studied as a balanced-anesthesia technique. This combination allows the provision of anesthesia without administering anesthetic drugs against which the Food and Drug Administration (FDA) issued a warning for the use in young children. Methods/Design In this phase-II, mono-center, prospective, single-blinded, randomized, controlled pilot trial, we will include a total of 80 children aged 0–3 years suffering from congenital heart disease and undergoing general anesthesia for elective diagnostic and/or interventional cardiac catheterization. Patients are randomized into two study groups, receiving either a combination of xenon and dexmedetomidine or mono-anesthesia with sevoflurane for the maintenance of anesthesia. The purpose of this study is to estimate the effect size for xenon-dexmedetomidine versus sevoflurane anesthesia with respect to the incidence of emergence delirium in children. We will also describe group differences for a variety of secondary outcome parameters including peri-interventional hemodynamics, emergence characteristics, incidence of postoperative vomiting, and the feasibility of a combined xenon-dexmedetomidine anesthesia in children. Discussion Sevoflurane is the most frequently used anesthetic in young children, but has been indicated as an independent risk factor in the development of emergence delirium. Xenon and dexmedetomidine have both been associated with a reduction in the incidence of emergence delirium. Combining xenon and dexmedetomidine has never been described as a balanced-anesthesia technique in children. Our pilot study will therefore deliver important data required for future prospective clinical trials. Trial registration EudraCT, 2018–002258-56. Registered on 20 August 2018. https://www.clinicaltrialsregister.eu .

Postoperative Complications

epidemiology

32977043

Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells

The continuous exposure of the colonic epithelium to high concentrations of bile acids may exert cytotoxic effects and has been related to pathogenesis of colon cancer. A better knowledge of the mechanisms by which bile acids induce toxicity is still required and may be useful for the development of new therapeutic strategies. We have studied the effect of deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) treatments in BCS-TC2 human colon adenocarcinoma cells. Both bile acids promote cell death, being this effect higher for CDCA. Apoptosis is detected after 30 min–2 h of treatment, as observed by cell detachment, loss of membrane asymmetry, internucleosomal DNA degradation, appearance of mitochondrial transition permeability (MPT), and caspase and Bax activation. At longer treatment times, apoptosis is followed in vitro by secondary necrosis due to impaired mitochondrial activity and ATP depletion. Bile acid-induced apoptosis is a result of oxidative stress with increased ROS generation mainly by activation of plasma membrane enzymes, such as NAD(P)H oxidases and, to a lower extent, PLA2. These effects lead to a loss of mitochondrial potential and release of pro-apoptotic factors to the cytosol, which is confirmed by activation of caspase-9 and -3, but not caspase-8. This initial apoptotic steps promote cleavage of Bcl-2, allowing Bax activation and formation of additional pores in the mitochondrial membrane that amplify the apoptotic signal.

Adenocarcinoma

pathology

41940539

Prevalence of toxoplasma encephalitis in AIDS patients treated with Didanosine hospitalised in a French infectious service.

In a previous work, we have showed in mice infected with an avirulent strain of Toxoplasma gondii and receiving a didanosine treatment, an important decrease of brain cysts. It is why, the purpose of this study was to investigate the effect of didanosine treatment on AIDS patients having developed Toxoplasma encephalitis. 60 patient reports were analyzed: 22 patients (group 1) did not received didanosine in their antiretroviral treatment and 38 (group 2) were treated with didanosine. The results showed that an antiretroviral therapy was prescribed for 93% of patients, 50% of them received only zidovudine and protease inhibitors were prescribed for 37%. The regimens given most frequently were those including zidovudine plus lamivudine or zidovudine plus indinavir. Among the group 1, 18% have had a relapse of Toxoplasma encephalitis. In the group 2, 37% of the patients suffered from one episode of TE while 16% have had two TE after the pause in their didanosine treatment, the maximum occurring between 4 and 24 months after the pause of didanosine. This study showed that didanosine seems to have an effect on cerebral cysts. Also, this work made a synthesis about the different treatment used in AIDS patients and the new molecules yet in development against T. gondii.

HIV Infections

drug therapy

22712562

Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium.

TNF has remarkable antitumor activities; however, therapeutic applications have not been possible because of the systemic and lethal proinflammatory effects induced by TNF. Both the antitumor and inflammatory effects of TNF are mediated by the TNF receptor p55 (p55TNFR) (encoded by the Tnfrsf1a gene). The antitumor effect stems from an induction of cell death in tumor endothelium, but the cell type that initiates the lethal inflammatory cascade has been unclear. Using conditional Tnfrsf1a knockout or reactivation mice, we found that the expression level of p55TNFR in intestinal epithelial cells (IECs) is a crucial determinant in TNF-induced lethal inflammation. Remarkably, tumor endothelium and IECs exhibited differential sensitivities to TNF when p55TNFR levels were reduced. Tumor-bearing Tnfrsf1a⁺⁺/⁻ or IEC-specific p55TNFR-deficient mice showed resistance to TNF-induced lethality, while the tumor endothelium remained fully responsive to TNF-induced apoptosis and tumors regressed. We demonstrate proof of principle for clinical application of this approach using neutralizing anti-human p55TNFR antibodies in human TNFRSF1A knockin mice. Our results uncover an important cellular basis of TNF toxicity and reveal that IEC-specific or systemic reduction of p55TNFR mitigates TNF toxicity without loss of antitumor efficacy.

Antineoplastic Agents

pharmacology

10550498

High-level expression of human dihydropteridine reductase (EC 1.6.99.7), without N-terminal amino acid protection, in Escherichia coli.

The cDNA coding for human dihydropteridine reductase [Dahl, Hutchinson, McAdam, Wake, Morgan & Cotton (1987) Nucleic Acids Res. 15, 1921-1936] was inserted downstream of tandem bacteriophage lambda PR and PL promoters in Escherichia coli vector pCE30. Since pCE30 also expresses the lambda c1857ts gene, transcription may be controlled by variation of temperature. The recombinant plasmid in an E. coli K12 strain grown at 30 degrees C, then at 45 degrees C, directed the synthesis of dihydropteridine reductase to very high levels. The protein was soluble, at least as active as the authentic human enzyme, and lacked the N-terminal amino acid protection.

Escherichia coli

enzymology

39794535

[Inhibitory effect of a third generation retinoid R8923 and all-trans retinoic acid on two-stage chemical carcinogenesis of BALB/3T3-A31 cells in vitro].

The inhibitory effect of a third generation retinoid R8923 and all-trans retinoic acid (RA) on malignant transformation of Balb/3T3-A31 cells induced by 3-methylcholanthrene (3-MCA) and 12-0-tetradecanoyl phorbol-13-acetate(TPA) was studied in paper. Malignant transformation of Balb/3T3-A31 cells was evaluated by scoring transformation foci and soft agar assay. Actively growing Balb/3T3-A31 cells (1.5 x 10(4) cells per 60-mm-diameter glass dish) were cultured in 5ml of Eagle's Minimum Essential Medium supplemented with 10 percent fetal bovine serum. Twenty-four hours after plating, the cells were treated with 3-MCA (2 micrograms/ml) for 72 hours. TPA was added into the medium at a concentration of 100 ng/ml for 2 weeks. Thirty-six days after cell plating, the transformation foci were counted and the soft agar assay of the cells isolated from each glass dish was performed. Results showed that there were 16.0 +/- 1.58 transformation foci/dish and the colony forming efficiency in soft agar assay was 138.6 +/- 14.47/10(3) cells in 3-MCA and TPA treated dishes (control group). When the cells were exposed to R8923 or RA (at a concentration of 10(-6) M), the transformation foci were 11.2 +/- 0.84 /dish and 9.2 +/- 1.10/dish respectively, and the corresponding colony forming efficiency values were 66.1 +/- 7.68/10(3) cells and 64.8 +/- 4.46/10(3) cells. They were significantly lower than that of the control group. These results demonstrated that R8923 and RA could effectively inhibit 3-MCA and TPA induced malignant transformation of Balb/3T3-A31 cells and suggested that R8923 is a potential drug for cancer chemoprevention.

Antineoplastic Agents

pharmacology

25511704

Assessment of Antimicrobial Usage and Residues in Commercial Chicken Eggs from Smallholder Poultry Keepers in Morogoro Municipality, Tanzania

Occurrence of antimicrobial residues in commercial chicken eggs was determined in Morogoro municipality between January and February 2007. Twenty smallholder farmers were interviewed on the types of antimicrobials, reasons of use and their awareness on antimicrobial withdrawal period. Seventy egg samples were collected for qualitative antimicrobial drug residues analysis by use of agar well diffusion and Delvotest SP® assays. It was found that farmers use antimicrobial drugs as prophylaxis and treatment of common chicken diseases namely fowl typhoid (85%), infectious bursa disease (Gumboro) (65%) infectious coryza (65%), collibacilosis (55%), coccidiosis (54%), Newcastle disease (50%), helminthosis (20%) and fowl pox (15%). Antimicrobials accounted for 85% of the drugs commonly used. It was also found that 65% of the farmers treat their chicken themselves. The common drugs were oxytetracycline (75%), egg booster (50%), amprolium (35%), sulphamethoxypyridazine (35%), sulphanilamide (25%), chlortetracyclines (10%), chloramphenicol (10%), sulphadiazine–trimethoprim (20%), duoxycycline (20%), sulphadiazine (25%) and flumequine (10%). Eighty per cent of the farmers had knowledge on antimicrobial withdrawal period sold eggs before withdrawal period and almost 85% were unaware of possible effects of antimicrobial residues in humans. All 70 eggs were positive to antimicrobial residues by Delvotest kit, but 21.4% positive with agar well diffusion test. It was concluded that the presence of antimicrobial residues in table eggs could be of public health significance to the egg consumers in Morogoro municipality.

Anti-Bacterial Agents

analysis

24848110

Quantification of contralateral breast dose and risk estimate of radiation-induced contralateral breast cancer among young women using tangential fields and different modes of breathing.

PURPOSE Whole breast irradiation with deep-inspiration breath-hold (DIBH) technique among left-sided breast cancer patients significantly reduces cardiac irradiation; however, a potential disadvantage is increased incidental irradiation of the contralateral breast. METHODS AND MATERIALS Contralateral breast dose (CBD) was calculated by comparing 400 treatment plans of 200 left-sided breast cancer patients whose tangential fields had been planned on gated and nongated CT data sets. Various anatomic and field parameters were analyzed for their impact on CBD. For a subgroup of patients (aged ≤45 years) second cancer risk in the contralateral breast (CB) was modeled by applying the linear quadratic model, compound models, and compound models considering dose-volume information (DVH). RESULTS The mean CBD was significantly higher in DIBH with 0.69 Gy compared with 0.65 Gy in normal breathing (P=.01). The greatest impact on CBD was due to a shift of the inner field margin toward the CB in DIBH (mean 0.4 cm; range, 0-2), followed by field size in magnitude. Calculation with different risk models for CBC revealed values of excess relative risk/Gy ranging from 0.48-0.65 vs 0.46-0.61 for DIBH vs normal breathing, respectively. CONCLUSION Contralateral breast dose, although within a low dose range, was mildly but significantly increased in 200 treatment plans generated under gated conditions, predominately due to a shift in the medial field margin. Risk modeling for CBC among women aged ≤45 years also pointed to a higher risk when comparing DIBH with normal breathing. This risk, however, was substantially lower in the model considering DVH information. We think that clinical decisions should not be affected by this small increase in CBD with DIBH because DIBH is effective in reducing the dose to the heart in all patients.

Breast Neoplasms

radiotherapy

11870864

Lack of associated renal anomalies in familial polythelia.

Sir .—Recent articles have addressed the possible association of supernumerary nipples with renal anomalies. Kenney et al, 1 examining Israeli infants, and Mimouni et al, 2 examining American term neonates, demonstrated no associated renal anomalies with isolated supernumerary nipples. However, Hersh et al 3 examined dysmorphic American children and Varsano et al 4 examined Israeli children referred to an emergency department. They demonstrated associated renal anomalies in 11% and 23%, respectively, of those children with a supernumerary nipple. A recent study by Meggyessy and Mehes 5 demonstrated renal abnormalities in 6 (8%) of 78 Hungarian patients hospitalized for illnesses unrelated to the urinary tract and healthy newborn infants. A limited number of instances of familial polythelia have been reported. Hersh et al 3 described two parentchild pairs with polythelia. Klinkerfuss 6 found polymastia with inconsistent polythelia in five females in four generations. Patient Report .—We report a case of an American

Kidney

abnormalities

26041840

Injured Fluoro-Jade-positive hippocampal neurons contain high levels of zinc after traumatic brain injury

Hippocampal damage contributes to cognitive dysfunction after traumatic brain injury (TBI). We previously showed that Fluoro-Jade, a fluorescent stain that labels injured, degenerating brain neurons, quantifies the extent of hippocampal injury after experimental fluid percussion TBI in rats. Coincidentally, we observed that injured neurons in the rat hippocampus also stained with Newport Green, a fluorescent dye specific for free ionic zinc. Here, we show that, regardless of injury severity or therapeutic intervention, the post-TBI population of injured neurons in rat hippocampal subfields CA1, CA3 and dentate gyrus is indistinguishable, both in numbers and anatomical distribution, from the population of neurons containing high levels of zinc. Treatment with lamotrigine, which inhibits presynaptic release of glutamate and presumably zinc that is co-localized with glutamate, reduced numbers of Fluoro-Jade-positive and Newport Green-positive neurons equally as did treatment with nicardipine, which blocks voltage-gated calcium channels through which zinc enters neurons. To confirm using molecular techniques that Fluoro-Jade and Newport Green-positive neurons are equivalent populations, we isolated total RNA from 25 Fluoro-Jade-positive and 25 Newport Green-positive pyramidal neurons obtained by laser capture microdissection (LCM) from the CA3 subfield, linearly amplified the mRNA and used quantitative ribonuclease protection analysis to demonstrate similar expression of mRNA for selected TBI-induced genes. Our data suggest that therapeutic interventions aimed at reducing neurotoxic zinc levels after TBI may reduce hippocampal neuronal injury.

Neurons

metabolism

51707438

A two-phenotype model of immune evasion by cancer cells.

We propose a model with two types of cancer cells differentiated by their defense mechanisms against the immune system. "Selfish" cancer cells develop defense mechanisms that benefit the individual cell, whereas "cooperative" cells deploy countermeasures that increase the chance of survival of every cell. Our phenotypes capture the two main features of the tumor's efforts to avoid immune destruction, crypticity against immune cells for the selfish cells, and tumor-induced immunosuppression for the cooperative cells. We identify steady states of the system and show that only homogeneous tumors can be stable in both size and composition. We show that under generic parameter values, a tumor of selfish cells is more benign than a tumor of cooperative cells, and that a treatment against cancer crypticity may promote immunosuppression and increase cancer growth.

Neoplasms

immunology

21294207

Sensitivites in vitro to antimicrobial drugs of bovine mycoplasmas isolated from respiratory and genital tracts.

A total of 155 Mycoplasma strains were examined for sensitivity to nine antibiotics and four nitrofurans by the agar dilution method. They consisted of 69 strains of Mycoplasma bovirhinis, 33 strains of M. bovigenitalium, 49 strains of Acholeplasma laidlawii and four strains of A. modicum isolated from the nasal secretions, tracheas and lungs of calves manifesting respiratory symptoms and from bovine genital tracts collected at a slaughterhouse. As a result, furamizole and mitomycin C showed the strongest growth-inhibiting effect on all the strains. They were followed in this effect by kitasamycin tartrate, spiramycin adipate, tylosin tartrate, tetracycline-HCl and chloramphenicol. Furthermore, these five drugs were followed in the effect by furazolidone, nitrofurantoin and sodium nifurstyrenate. Fradiomycin sulfate and kanamycin sulfate showed only little effect on all the strains. Erythromycin lactobionate showed a strong growth-inhibiting effect on the Acholeplasma strains, but not on the Mycoplasma strains. There were some cross resistant strains of the Acholeplasma species to the effects of the macrolides.

Anti-Bacterial Agents

pharmacology

7393399

CHANGES IN THE DNA SYNTHESIS PATTERN OF PARAMECIUM WITH INCREASED CLONAL AGE AND INTERFISSION TIME

The clonal age in paramecia refers to the total number of vegetative divisions a clone has undergone since its origin at autogamy (self-fertilization). As clonal age increases, the interfission time usually increases. The DNA synthesis pattern of cells of different ages was compared by autoradiographic analysis of the DNA synthesis of synchronized cells at various time intervals during the cell cycle (from one division to the next). The study showed that the G1 period (the lag in DNA synthesis post division) was constant, irrespective of interfission time or clonal age; but the duration of the DNA synthesis period increased with increased interfission time or clonal age. Therefore, we have shown for the first time that the G1 period is fixed, and the S period is increased in a eukaryotic unicellular organism as a function of interfission time and clonal age.

DNA

biosynthesis

10805865

Therapeutic Results of Abdominoperineal Resection in the Prone Jackknife Position for T3–4 Low Rectal Cancers

ObjectiveTo evaluate the therapeutic results of abdominoperineal resections in the prone jackknife position for T3–4 low rectal cancers.MethodsFrom January 2002 to January 2011, 536 patients with T3–T4 low rectal cancer underwent abdominoperineal resection. Two hundred forty-three were treated in the Lloyd-Davies position and 293 in the prone jackknife position. Clinicopathological data and survival of the two groups were analyzed retrospectively.ResultsAbdominoperineal resections in the prone jackknife position group were associated with significantly less blood loss (124 ± 50.68 vs 210.67 ± 83.32 ml, P < 0.001) and shorter operation times (3.10 ± 1.08 vs 3.82 ± 1.43 h, p = 0.010) than those in Lloyd-Davies position group. The total local recurrence rate is 8.4 % (45/536). The local recurrence rate in the prone jackknife position group was significantly lower than in the Lloyd-Davies position group (5.5 vs 11.9 %, P < 0.001). By multivariate regression analysis, depth of tumor invasion (P = 0.032), CRM (P < 0.001), and position (P = 0.015) were found to be independent risk factors for local recurrence. Multivariate Cox regression survival analysis, lymph node metastasis, and CRM (P < 0.001) were proven to be the major independent prognostic factors for T3–T4 low rectal cancer patients.ConclusionsAbdominoperineal resection in the prone jackknife position for T3–T4 low rectal cancers is feasible and has a lower local recurrence.

Adenocarcinoma

surgery

9138455

[Expressive features of HBsAg and HBcAg in the livers of chronic hepatitis B and its clinical significance].

OBJECTIVE To investigate the necessity of detecting on the expressive intensity and pattern of HBsAg and HBcAg in the livers of chronic hepatitis B. METHODS HBsAg and HBcAg were detected in paraffin-embedded liver tissue by EnVision immunohistochemistry. Serum hepatitis B virus DNA (HBV DNA) was tested by real-time quantitative polymerase chain reaction. The degrees of hepatic inflammatory activity (grade) and fibrosis (stage) of liver biopsies were determined according to the standard of the Chinese program of prevention and treatment of viral hepatitis. RESULTS The expression of HBsAg was not correlated with the grade, the stage and the levels of serum HBV DNA (P > 0.05). Liver HBcAg expressive intensity was not correlated with the grade (r=0.02, P > 0.05), while negatively correlated with the stage (r=0.28, P < 0.01) and positively correlated with the serum HBV DNA levels (r=0.53, P < 0.01). Liver HBcAg expressive pattern was negatively correlated with the grade (r=-0.27, P < 0.01). The grade in cytoplasmic pattern group was higher than in nuclear pattern group and in mixed pattern group (P < 0.01), and that in mixed pattern group was higher in nuclear pattern group (P < 0.01). Liver HBcAg expressive pattern was negatively correlated with the stage (r=-0.23, P < 0.01). The stage in cytoplasmic pattern group was higher than in nuclear pattern group and in mixed pattern group (P < 0.05). Liver HBcAg expressive pattern was positively correlated with the levels of serum HBV DNA (r=0.22, P < 0.01). CONCLUSION Distinguishing the expressive intensity and pattern of HBsAg and HBcAg in the liver of chronic hepatitis B may not help understand the degree of hepatic lesion. The detection of HBcAg in liver tissue of CHB may be beneficial for the antiviral therapy.

Liver

pathology

20581562

Modified programme of in-patient (phase I) cardiac rehabilitation after acute myocardial infarction

A group of 61 men who suffered from myocardial infarction (MI) were divided into two groups: group A (31 patients post MI, one day at intensive care unit (ICU), no β-blockers, physical therapy according to a seven-day programme) and group B (30 patients post MI, two days at ICU, with β-blockers, physical therapy according to a seven-day programme). Results from both groups were compared with a control group (C) (38 patients post MI, three days at ICU, physical therapy according to a longer ten-day graded programme). The objective of this study was to assess the efficacy of a proposed modified rehabilitation programme in patients after acute MI on the basis of a submaximal stress test performed on a cycle ergometer and to find out which stress test parameters might be used for the selection of an appropriate phase 2 rehabilitation programme. The performed analysis of correlation between exercise and resting parameters showed statistical relevancy with regard to systolic blood pressure in group A. Maximal load (WATs), metabolic cost (METs), maximal heart rate (beats/min), stress-test time (T-test) and time of normalization for the exercise parameters (tn) are the parameters of the stress test that should be taken into consideration for appropriate selection of an out-patient (phase 2) rehabilitation programme.

Myocardial Infarction

rehabilitation

32877748

Immunogenicity of Mycobacterium tuberculosis RD1 region gene products in infected cattle

Current immuno‐diagnostic tests for the detection of Mycobacterium bovis infection in cattle rely on the use of tuberculin PPD as antigens. However, the use of a cattle vaccine is effectively prohibited because BCG, the only potentially available cattle TB vaccine, compromises the current tuberculin test. The main objective of this study was to identify specific antigens, which could increase the test sensitivity to levels achieved with tuberculin. Our approach utilized the availability of the genome sequences of Mycobactereium tuberculosis and BCG by applying principles of comparative genomics to the identification of species‐specific antigens. Eight open‐reading frames (Rv3871 to Rv3878) encoding for putative antigens in the RD1 region of the M. tuberculosis genome, which is deleted in all strains of BCG, were selected and screened in the form of pools of synthetic peptides for immunological reactivity (antigen induced proliferation and IFN‐γ secretion) with peripheral blood mononuclear cells from cattle experimentally infected with M. bovis. Our results confirm the immunodominant role of two RD1 region products, CFP‐10 (Rv3874) and ESAT‐6 (Rv3875). In addition, we were able to identify 3 more antigens (Rv3871, Rv3872 and Rv3873), which induced immunological reactivity in PBMC from more than 50%M. bovis of infected cattle.

Bacterial Proteins

immunology

32253376

Physicochemical principles that regulate the competition between functional and dysfunctional association of proteins

To maintain protein homeostasis, a variety of quality control mechanisms, such as the unfolded protein response and the heat shock response, enable proteins to fold and to assemble into functional complexes while avoiding the formation of aberrant and potentially harmful aggregates. We show here that a complementary contribution to the regulation of the interactions between proteins is provided by the physicochemical properties of their amino acid sequences. The results of a systematic analysis of the protein–protein complexes in the Protein Data Bank (PDB) show that interface regions are more prone to aggregate than other surface regions, indicating that many of the interactions that promote the formation of functional complexes, including hydrophobic and electrostatic forces, can potentially also cause abnormal intermolecular association. We also show, however, that aggregation-prone interfaces are prevented from triggering uncontrolled assembly by being stabilized into their functional conformations by disulfide bonds and salt bridges. These results indicate that functional and dysfunctional association of proteins are promoted by similar forces but also that they are closely regulated by the presence of specific interactions that stabilize native states.

Proteins

chemistry

46155475

Antibiotic consumption in Turkish hospitals; a multi-centre point prevalence study

This multi-centre study aimed to determine the antibiotic consumption in Turkish hospitals by point prevalence. Antibiotic consumption of 14 centres was determined using the DDD method. Among hospitalized patients, 44.8% were using antibiotics and the total antibiotic consumption was 674.5 DDD/1000 patient-days (DPD). 189.6 (28%) DPD of the antibiotic consumption was restricted while 484.9 (72%) DPD was unrestricted. Carbapenems (24%) and beta lactam/beta lactamase inhibitors (ampicillin-sulbactam or amoxicillin-clavulanate; 22%) were the most commonly used restricted and unrestricted antibiotics. Antibiotics were most commonly used in intensive care units (1307.7 DPD). Almost half of the hospitalized patients in our hospitals were using at least one antibiotic. Moreover, among these antibiotics, the most commonly used ones were carbapenems, quinolones and cephalosporins, which are known to cause collateral damage. We think that antibiotic resistance, which is seen at considerably high rates in our hospitals, is associated with this level of consumption.

Anti-Bacterial Agents

therapeutic use

14600126

RnlB Antitoxin of the Escherichia coli RnlA-RnlB Toxin–Antitoxin Module Requires RNase HI for Inhibition of RnlA Toxin Activity

The Escherichia coli RnlA-RnlB toxin–antitoxin system is related to the anti-phage mechanism. Under normal growth conditions, an RnlA toxin with endoribonuclease activity is inhibited by binding of its cognate RnlB antitoxin. After bacteriophage T4 infection, RnlA is activated by the disappearance of RnlB, resulting in the rapid degradation of T4 mRNAs and consequently no T4 propagation when T4 dmd encoding a phage antitoxin against RnlA is defective. Intriguingly, E. coli RNase HI, which plays a key role in DNA replication, is required for the activation of RnlA and stimulates the RNA cleavage activity of RnlA. Here, we report an additional role of RNase HI in the regulation of RnlA-RnlB system. Both RNase HI and RnlB are associated with NRD (one of three domains of RnlA). The interaction between RnlB and NRD depends on RNase HI. Exogenous expression of RnlA in wild-type cells has no effect on cell growth because of endogenous RnlB and this inhibition of RnlA toxicity requires RNase HI and NRD. These results suggest that RNase HI recruits RnlB to RnlA through NRD for inhibiting RnlA toxicity and thus plays two contrary roles in the regulation of RnlA-RnlB system.

Escherichia coli

enzymology

58537011

Weighting Nonprobability and Probability Sample Surveys in Describing Cancer Catchment Areas

Background: The Population Health Assessment initiative by NCI sought to enhance cancer centers’ capacity to acquire, aggregate, and integrate data from multiple sources, as well as to plan, coordinate, and enhance catchment area analysis activities. Methods: Key objectives of this initiative are pooling data and comparing local data with national data. A novel aspect of analyzing data from this initiative is the methodology used to weight datasets from sites that collected both probability and nonprobability samples. This article describes the methods developed to weight data, which cancer centers collected with combinations of probability, and nonprobability sampling designs. Results: We compare alternative weighting methods in particular for the hybrid probability and nonprobability sampling designs employed by different cancer centers. We also include comparisons of local center data with national survey data from large probability samples. Conclusions: This hybrid approach to calculating statistical weights can be implemented both within cancer centers that collect both probability and nonprobability samples with common measures. Aggregation can also apply to cancer centers that share common data elements, and target similar populations, but differ in survey sampling designs. Impact: Researchers interested in local versus national comparisons for cancer surveillance and control outcomes should consider various weighting approaches, including hybrid approaches, when analyzing their data.

Neoplasms

epidemiology

9358419

Vulvar adenocarcinoma: visual resemblance to a vulvar abscess

Abscesses of the vulvar and perineal regions are fairly common and very painful clinical entities warranting urgent surgical drainage. Here we describe the case of a woman who visited her primary care physician with symptoms of redness, swelling and severe pain over the right vulva (figure 1). As the patient had first noticed these symptoms less than a week previously, their apparently acute onset suggested a clinical diagnosis of …

Adenocarcinoma

diagnosis

52923555

Systematic Analysis of Transmitter Coexpression Reveals Organizing Principles of Local Interneuron Heterogeneity

Abstract Broad neuronal classes are surprisingly heterogeneous across many parameters, and subclasses often exhibit partially overlapping traits including transmitter coexpression. However, the extent to which transmitter coexpression occurs in predictable, consistent patterns is unknown. Here, we demonstrate that pairwise coexpression of GABA and multiple neuropeptide families by olfactory local interneurons (LNs) of the moth Manduca sexta is highly heterogeneous, with a single LN capable of expressing neuropeptides from at least four peptide families and few instances in which neuropeptides are consistently coexpressed. Using computational modeling, we demonstrate that observed coexpression patterns cannot be explained by independent probabilities of expression of each neuropeptide. Our analyses point to three organizing principles that, once taken into consideration, allow replication of overall coexpression structure: (1) peptidergic neurons are highly likely to coexpress GABA; (2) expression probability of allatotropin depends on myoinhibitory peptide expression; and (3) the all-or-none coexpression patterns of tachykinin neurons with several other neuropeptides. For other peptide pairs, the presence of one peptide was not predictive of the presence of the other, and coexpression probability could be replicated by independent probabilities. The stochastic nature of these coexpression patterns highlights the heterogeneity of transmitter content among LNs and argues against clear-cut definition of subpopulation types based on the presence of single neuropeptides. Furthermore, the receptors for all neuropeptides and GABA were expressed within each population of principal neuron type in the antennal lobe (AL). Thus, activation of any given LN results in a dynamic cocktail of modulators that have the potential to influence every level of olfactory processing within the AL.

Brain

metabolism

42602533

Acute tubulointerstitial nephritis associated with Yersinia pseudotuberculosis infection.

Two siblings infected with Yersinia pseudotuberculosis suffered from acute renal failure about 2 weeks after the onset of the disease. Renal histology in both siblings showed acute tubulointerstitial nephritis. Yersinia pseudotuberculosis type VB was isolated from feces of one of them, antibodies to Yersinia pseudotuberculosis type VB in their sera were elevated. The results of the present study suggest that acute renal failure complicating infections with Yersinia pseudotuberculosis is due to acute tubulointerstitial nephritis.

Kidney

pathology

41428437

REPRODUCTION AMONG FEMALE MENTAL PATIENTS: OBSTETRIC COMPLICATIONS AND PHYSICAL SIZE OF OFFSPRING

Rates of obstetric complications, deviations in prenatal development and predischarge neonatal disturbances were studied in 171 reproductions to female psychiatric patients and 171 reproductions to demographicallymatched control women from the same hospital delivery series. The patients were diagnostically categorized as ‘endogenous psychotics’ (process schizophrenia, manic‐depressive psychosis, schizophrenic‐like‐psychoses) and ‘other patients’ (psychopathy and diverse diagnoses). No significant difference was found between any patient group vs. its control group on rates of total pregnancy complications, labor‐birth complications, placental characteristics, predischarge neonatal disturbances or all complications. Significantly fewer of the offspring of endogenous psychotics, as contrasted with controls, were markedly preterm. Additional results concerning the relationship between complications and offspring sex and between complications and timing of mother's first psychiatric hospitalization are presented.

Mental Disorders

complications

27354296

[99mTechnetium-diethylenetriaminepentaacetic acid renoscintigraphy as a measure of renal function and urodynamics after uretero-ileoceco-proctostomy].

Ten patients having a uretero-ileocecoproctostomy (ileocecorectal bladder) were evaluated by 99mtechnetium diethylenetriaminepantaacetic acid renoscintigraphy, which was repeated at an approximately 1 year interval in 7 patients. The computed total glomerular filtration rates at the 1st and 2nd surveys were 100 +/- 23.2 and 92.7 +/- 23.0 ml/min (mean +/- S.D.), respectively indicating a minimal change with no statistically significant difference. The normal or incompletely obstructive renogram patterns were consistent with the pyelographic findings in 27 of 28 renal units, and 5 of 6 renal units with dilated nonobstructive renograms subsequently became normal both on the renograms and pyelograms. Comparing the data in the 1st and 2nd surveys, the frequency of colonic reflux decreases from 8/10 to 3/7 of the patients, the rectal bladder capacity increased from 82 +/- 18.8% to 92 +/- 20.8% of the excreted urine, and the total residual urine rate decreased from 40.4 +/- 12.9% to 28.0 +/- 16.6% (p = 0.1298), respectively. The results indicate that the ileocecorectal bladder, though it has no antireflux mechanism against colonic regurgitation, well functions as an internal continent urinary reservoir. Also, since this comprehensive information is obtained by a single procedure, the radionuclide evaluation can be practiced as a cost-beneficial measure for follow-up of patients with urinary diversions.

Kidney

physiopathology

20338077

Cytotoxic therapy-induced D-xylose malabsorption and invasive infection during remission-induction therapy for acute myeloid leukemia in adults.

PURPOSE To study the sequential changes in the intestinal absorption of an oral pentose probe, D-xylose, in patients receiving therapy for untreated acute myeloid leukemia (AML), and to correlate these changes to infectious morbidity. PATIENTS AND METHODS Serial D-xylose absorption studies were conducted in 110 consecutive adult patients admitted to a university-affiliated tertiary care hospital for remission-induction therapy for untreated newly diagnosed AML. Serial serum D-xylose levels were obtained 1 hour after a 5-g oral dose of D-xylose at baseline and weekly for 4 weeks until marrow recovery. These results were correlated with invasive infection using multivariate techniques. RESULTS The mean (+/- SEM) serum D-xylose levels were 0.88 +/- 0.03, 0.69 +/- 0.03, 0.58 +/- 0.02, 0.53 +/- 0.02, and 0.73 +/- 0.02 mmol/L at baseline and weeks 1 to 4, respectively (P < .0001, analysis of variance [AN-OVA]). Time to malabsorption varied with induction regimen (P = .007, log-rank test). Bloodstream infections during week 2 correlated with malabsorption (P = .007). Neutropenic enterocolitis correlated independently with induction regimen (P = .009), malabsorption at week 2 (P = .02), and the development of candidemia (P = .005). Hepatosplenic fungal infection correlated with induction regimen (P = .03), malabsorption at week 2 (P = .02), and fever at diagnosis (P = .003). Malabsorption was unrelated to the duration of severe neutropenia and the administration of parenteral nutrition. CONCLUSION Serial D-xylose absorption studies in subjects with AML produced a characteristic profile of cytotoxic therapy-related damage to the functional integrity of the intestinal epithelium that was regimen dependent, myelosuppression independent, and predictive for invasive infectious complications. Further study to validate these observations appears warranted.

Antineoplastic Agents

adverse effects

24391733

The ability of CBCL DSM-oriented scales to predict DSM-IV diagnoses in a referred sample of children and adolescents

The majority of studies examining associations between clinical–diagnostic and empirical-quantitative approaches have concentrated only on the target diagnosis without taking into account any possible co-variation of psychopathological traits, which is intrinsic to child psychopathology. The ability of child behaviour checklist (CBCL) DSM-oriented scales (DOSs) to predict target and other DSM diagnoses, taking into consideration the covariation of psychopathological traits, was analysed by logistic regression analysis. Corresponding odds ratio (OR) was used as indicator of the strength of the relationship between the clinical score in DOSs and the presence of DSM-IV diagnoses. Logistic regression allowed us to consider multiple scales simultaneously, thus addressing the problem of co-occurrence of psychopathological traits, and to include gender and age as covariates. The sample consisted of 360 children and adolescents aged 6–16 years, consecutively referred for behavioural and emotional problems. As a whole, the CBCL DOSs seem to be more specific but with a weaker association with DSM-IV diagnoses than syndrome scales, and with some distinctive features: clinical scores in the anxiety DOS suggest a diagnosis of both anxiety and mood disorder; clinical scores in the somatic problems DOS are very strong and specific predictors for diagnosis of separation anxiety disorder; clinical scores in the oppositional defiant problems DOS are not only predictors of the oppositional defiant disorder but are also strong predictors of generalized anxiety disorder; clinical scores in the conduct problems DOS are a specific and strong predictor for oppositional defiant disorder. Results confirm the clinical usefulness of CBCL and suggest using both syndrome and DOS scales for a complete and accurate assessment of children and adolescents.

Mental Disorders

diagnosis

17390103

Respiratory muscle strength effect on linear and nonlinear heart rate variability parameters in COPD patients

Introduction Chronic obstructive pulmonary disease (COPD) is recognized as a multisystemic inflammatory disease associated with extrapulmonary comorbidities, including respiratory muscle weakness and cardiovascular and cardiac autonomic regulation disorders. We investigated whether alterations in respiratory muscle strength (RMS) would affect cardiac autonomic modulation in COPD patients. Methods This study was a cross-sectional study done in ten COPD patients affected by moderate to very severe disease. The heart rate variability (HRV) signal was recorded using a Polar cardiofrequencimeter at rest in the sitting position (10 minutes) and during a respiratory sinus arrhythmia maneuver (RSA-M; 4 minutes). Linear analysis in the time and frequency domains and nonlinear analysis were performed on the recorded signals. RMS was assessed using a digital manometer, which provided the maximum inspiratory pressure (PImax) and the maximum expiratory pressure (PEmax). Results During the RSA-M, patients presented an HRV power increase in the low-frequency band (LFnu) (46.9±23.7 vs 75.8±27.2; P=0.01) and a decrease in the high-frequency band (HFnu) (52.8±23.5 vs 24.0±27.0; P=0.01) when compared to the resting condition. Significant associations were found between RMS and HRV spectral indices: PImax and LFnu (r=−0.74; P=0.01); PImax and HFnu (r=0.74; P=0.01); PEmax and LFnu (r=−0.66; P=0.01); PEmax and HFnu (r=0.66; P=0.03); between PEmax and sample entropy (r=0.83; P<0.01) and between PEmax and approximate entropy (r=0.74; P=0.01). Using a linear regression model, we found that PImax explained 44% of LFnu behavior during the RSA-M. Conclusion COPD patients with impaired RMS presented altered cardiac autonomic control, characterized by marked sympathetic modulation and a reduced parasympathetic response; reduced HRV complexity was observed during the RSA-M.

Lung

physiopathology

24617056

Metabolism of primaquine by liver homogenate fractions. Evidence for monoamine oxidase and cytochrome P450 involvement in the oxidative deamination of primaquine to carboxyprimaquine.

The role of monoamine oxidase (MAO) and cytochrome P450 (P450) in the oxidative deamination of primaquine by rat liver fractions was studied. Rat liver fractions including liver homogenate, mitochondria, microsomes and 100,000 g supematant fractions were prepared from a pool of rat livers and characterised using benzylamine as a probe for MAO activity and N,N-dimethylbenzamide as a probe for P450 N-dealkylation activity. Incubation of all fractions with primaquine yielded carboxyprimaquine as the only metabolite detectable by HPLC. The mitochondrial fraction, which contained MAO activity but not P450 activity, presented the highest Vmax/K(M) value for the formation of carboxyprimaquine (8.5 x 10(-6) dm3mg(-1)h(-1). A substantially lower Vmax/K(M) value (1.3 x 10(-6) dm3mg(-1)h(-1)) was obtained in the microsomal fraction, which contained P450 but not MAO activity. The liver homogenate fraction presented a similar value (1.8 x 10(-6) dm3mg(-1)h(-1), though it contained both enzyme systems. Incubations of all the fractions that presented MAO activity, in presence of the MAO inhibitor pargiline, resulted in a marked inhibition of primaquine oxidation. P450 inhibitor SKF 525-A effectively inhibited primaquine metabolism in the microsomal fraction but inhibition in the liver homogenate was less effective. The results are consistent with an important role for MAO in primaquine biotransformation, though clearly metabolism by P450 has a contribution role.

Liver

enzymology

22446272

Molecular typing of Staphylococcus aureus clinical isolates by pulsed-field gel electrophoresis, staphylococcal cassette chromosome mec type determination and dissemination of antibiotic resistance genes.

Pulsed-field gel electrophoresis (PFGE) of SmaI macrorestriction fragments of genomic DNA as well as staphylococcal cassette chromosome mec (SCCmec) typing for mecA-carrying isolates were used to study the distribution of clonal types among 177 Staphylococcus aureus clinical isolates recovered in a Spanish hospital between 2000 and 2003. Five major clonal types (P1 to P5) were identified by PFGE, with one of them (P1) comprising the majority of strains (47.5%). According to SCCmec typing, SCCmec type IVA was the most prevalent type, showing increasing prevalence in the hospital setting with respect to other pandemic clones. One SCCmec pattern was detected in different PFGE types, which demonstrates that the latter is a major discriminative typing method. Three novel SCCmec elements or variants were found, each in a different PFGE type. Oxacillin (methicillin)-resistant and -susceptible S. aureus (MRSA and MSSA, respectively) strains were detected showing identical PFGE patterns, suggesting horizontal transfer of mecA to MSSA and/or mecA deletion from MRSA. Persistence of several S. aureus clones throughout the years within the same hospital environment was also observed.

Bacterial Proteins

genetics

206366771

Mass spectrometry‐based proteomics strategies for protease cleavage site identification

Protease‐catalyzed hydrolysis of peptide bonds is one of the most pivotal post‐translational modifications fulfilling manifold functions in the regulation of cellular processes. Therefore, dysregulation of proteolytic reactions plays a central role in many pathophysiological events. For this reason, understanding the molecular mechanisms in proteolytic reactions, in particular the knowledge of proteases involved in complex processes, expression levels and activity of protease and knowledge of the targeted substrates are an indispensable prerequisite for targeted drug development. The present review focuses on mass spectrometry‐based proteomic methods for the analysis of protease cleavage sites, including the identification of the hydrolyzed bonds as well as of the surrounding sequence. Peptide‐ and protein‐centric approaches and bioinformatic tools for experimental data interpretation will be presented and the major advantages and drawbacks of the different approaches will be addressed. The recent applications of these approaches for the analysis of biological function of different protease classes and potential future directions will be discussed.

Proteins

metabolism

42949867

[Palliative care in Seirei Mikatahara General Hospital Department of Palliative and Supportive Care, Seirei Mikatahara General Hospital].

This paper illustrates a brief review of the development process of the palliative care team at the Seirei Mikatahara General Hospital. Palliative care team has been first instituted in 2002, and currently providing general support for cancer patients receiving chemotherapy not only for terminally ill patients. In future, we would start a regional palliative care program, including community palliative care team, to provide appropriate palliative care for all cancer population.

Neoplasms

therapy

81983194

Chitosan nanoparticles enhance the antibacterial activity of the native polymer against bovine mastitis pathogens.

Staphylococcus is the most commonly isolated genus from animals with intramammary infections, and mastitis is the most prevalent disease that affects dairy cows in many countries. These pathogens can live in biofilms, a self-produced matrix, which allow them evade the innate immune system and the antibiotic therapy, thereby producing persistent infections. The aim of this study was to explore the antimicrobial potential of chitosan nanoparticles (Ch-NPs) obtained by the reverse micellar method. We found that the nanoformulation developed presents antimicrobial activity against mastitis pathogens in a dose-dependent manner. Moreover, different experiments corroborated that the antimicrobial effectiveness of Ch-NP was greater than that shown by the native polymer used in the preparation of these nanocomposites. Ch-NPs caused membrane damage to bacterial cells and inhibited bacterial biofilm formation, without affecting the viability of bovine cells. These findings show the great potential of Ch-NPs as therapeutic agent for bovine mastitis treatment.

Anti-Bacterial Agents

pharmacology

28548337

Lv2, a Novel Postentry Restriction, Is Mediated by both Capsid and Envelope

ABSTRACT The characterization of restrictions to lentivirus replication in cells identifies critical steps in the viral life cycle and potential therapeutic targets. We previously reported that a human immunodeficiency virus type 2 (HIV-2) isolate was restricted to infection in some human cells, which led us to identify a step in the life cycle of HIV-2 detected after reverse transcription but prior to nuclear entry. The block is bypassed with a vesicular stomatitis virus glycoprotein G (VSV-G) envelope (A. McKnight et al., J. Virol. 75:6914-6922, 2001). We hypothesized that, although the restriction is apparent at a post-reverse transcription step, the lack of progress results from a failure of the virus to reach a cellular compartment with access to the nucleus. Here we analyzed molecular clones of the restricted virus, MCR, and an unrestricted virus, MCN. Using sequence analysis and gene swapping, we mapped the viral determinants to gag and env. Site-directed mutagenesis identified a single amino acid at position 207 in CA to be responsible for the gag restriction. Pseudotype experiments indicate that this step is also important for the infection of cells by HIV-1. The HIV-1 NL4.3 core is restricted if supplied with a restricted MCR envelope but not with VSV-G. Also the NL4.3 envelope rescues the restricted core of HIV-2 MCR. Abrogation experiments with MLV demonstrate that the restriction is distinct from Fv1/Ref1/Lv1. We propose that this represents a new lentiviral restriction, Lv2. Thus, the envelope and capsid of HIV act to ensure that the virus is delivered into an appropriate cellular compartment that allows postentry events in viral replication to proceed efficiently.

Proteins

metabolism

4078105

Developmental broadening of inhibitory sensory maps

Sensory maps are created by networks of neuronal responses that vary with their anatomical position, such that representations of the external world are systematically and topographically organized in the brain. Current understanding from studying excitatory maps is that maps are sculpted and refined throughout development and/or through sensory experience. Investigating the mouse olfactory bulb, where ongoing neurogenesis continually supplies new inhibitory granule cells into existing circuitry, we isolated the development of sensory maps formed by inhibitory networks. Using in vivo calcium imaging of odor responses, we compared functional responses of both maturing and established granule cells. We found that, in contrast to the refinement observed for excitatory maps, inhibitory sensory maps became broader with maturation. However, like excitatory maps, inhibitory sensory maps are sensitive to experience. These data describe the development of an inhibitory sensory map as a network, highlighting the differences from previously described excitatory maps.

Neurons

physiology

701482

Systemic safety of fluticasone furoate/vilanterol combination

The recent article by Busse et al 1 on the safety of fluticasone furoate/vilanterol combination (FF/VI) in asthma reported no significant changes in geometric mean 24 h urinary cortisol (24UC) compared with baseline, perhaps giving a false impression that FF is devoid of systemic adverse effects. The interpretation of these data should be put in context of the patients who were already taking inhaled corticosteroids (ICS 500–1000μg/day) and, as such, would have suppressed adrenal function prior to randomisation …

Asthma

drug therapy

77074173

[The clinical efficacy of treating patients with nonspecific lung diseases using low-energy laser irradiation and intrapulmonary drug administration].

Intrapulmonary administration of glucocorticosteroids and antibiotics combined with low-energy laser radiation was employed in the treatment of patients with infection-dependent bronchial asthma in the phase of exacerbation and frequent asphyxia attacks, long medical history and of patients with lung abscesses. The purpose of the work was to study and compare the clinical effectiveness of the method in the gravest group of patients suffering from nonspecific pulmonary diseases: suppurative (acute lung abscess) and infectious allergic (infection-dependent bronchial asthma of medium gravity with frequent attacks, long medical history, tendency towards aggravation of the status and low efficacy of broncholytics). The results of the treatment and follow-up have shown that the use of the combined treatment suggested is most optimal in patients with acute lung abscesses (the percentage of the cured is 94.1). In patients with infection-dependent bronchial asthma, the use of laser therapy combined with intrapulmonary administration of steroids also noticeably improved the clinical, functional and immunological characteristics, prolonged the phase of remission.

Anti-Bacterial Agents

administration & dosage

1644755

Preoperative glucose as a screening tool in patients without diabetes.

BACKGROUND Although hyperglycemia has been associated with poor postoperative outcomes, preoperative hyperglycemia is not used as a screening tool in patients without diabetes. We evaluated preoperative glucose as a marker for postoperative outcomes in patients without diabetes to assess its usefulness as a potential screening tool. MATERIALS AND METHODS Clinical characteristics for a sample of 6683 patients without diabetes who underwent nonemergent vascular and general surgery were collected from the American College of Surgeons National Surgical Quality Improvement Program, Brigham and Women's Hospital database. Last glucose measured within 30 d before surgery was the main predictor variable with postoperative infection within 30 d as the primary outcome. RESULTS For patients without known diabetes with preoperative glucose of 100-139 and 140-179 mg/dL, postoperative infection rates were significantly higher (9.33% and 10.16%, respectively) than that of patients with preoperative glucose of 70-99 mg/dL (5.62%, P < 0.001). The risk-adjusted odds of postoperative infection increased by 40% (95% CI, 13%-72%) for each 40 mg/dL increase in preoperative glucose over the range 70-179 mg/dL. Follow-up data demonstrated that 15% of patients with preoperative glucose ≥100 mg/dL were diagnosed with diabetes within 1 y after surgery. CONCLUSIONS In patients without known diabetes, preoperative glucose is a significant marker for postoperative complications even at moderate levels of hyperglycemia. Some of these patients likely had prediabetes or unrecognized diabetes at the time of surgery. Further studies are needed to determine whether such screening and follow-up of preoperative hyperglycemia in all patients would be effective in lowering complication rates.

Postoperative Complications

epidemiology

2761231

Control of cytosolic calcium activity during low sodium exposure in cultured chick heart cells.

We investigated the roles of sodium-calcium exchange, sarcoplasmic reticulum, and mitochondria in Cai homeostasis in cultured chick ventricular cells. Specifically, the influence of low sodium medium on contractile state, calcium fluxes, and cytosolic free [Ca] [( Ca]i) was examined. [Ca]i was measured using fura-2. Mean [Ca]i in control medium was 126 +/- 14 nM. Exposure of cells to sodium-free or sodium- and calcium-free medium (choline-substituted) resulted in contracture development, which returned toward the baseline level over 2-3 minutes. The Nao-free contracture was associated with a tenfold increase in [Ca]i (1,280 +/- 110 nM) followed by a gradual decrease to a level fourfold above control [Ca]i (460 +/- 58 nM). Nao- and Cao-free contracture was associated with a fivefold increase in [Ca]i (540 +/- 52 nM) followed by a rapid decrease to below 80 nM. Sodium-free medium failed to produce an increase in [Ca]i or contracture in cells preexposed to calcium-free medium, although caffeine, when subsequently added to sodium- and calcium-free medium, was able to elicit a transient increase in [Ca]i and contracture. Brief, 5-second preperfusion of cells with La3+ (1 mM) or EGTA (1 mM) abolished the Nao-free contracture and the increase in [Ca]i. In the presence of 20 mM caffeine, removal of Nao resulted in minimal changes in the resting position of the cell although 45Ca uptake and [Ca]i were increased in response to sodium-free medium; the subsequent decrease in [Ca]i was greatly slowed. Addition of caffeine during the relaxation phase of the sodium-free contracture produced an additional transient contracture and transient increase in [Ca]i. Ryanodine (1 microM) abolished this effect of caffeine. Caffeine or ryanodine abolished Nao- and Ca-free contracture. CCCP (2 microM), a potent oxidative phosphorylation inhibitor, did not significantly affect calcium efflux rate. In the presence of 2 microM CCCP, removal of sodium resulted in an augmented contracture signal and a rise in [Ca]i, followed by a slow decrease. We conclude that removal of extracellular sodium enhances transsarcolemmal entry of calcium via sodium-calcium exchange, but this effect alone does not lead to the development of sodium-free contracture. Calcium displaceable by lanthanum or EGTA appears to contribute to Nao-free or Nao- and Cao-free contracture. Studies using caffeine and ryanodine suggest that removal of Nao leads to release of calcium from the sarcoplasmic reticulum (presumably via calcium-induced calcium release).(ABSTRACT TRUNCATED AT 400 WORDS)

Calcium

metabolism

20252093

[Successful treatment of a patient with multidrug resistant Acinetobacter baumannii meningitis with high dose ampicillin-sulbactam].

Acinetobacter baumannii is an important pathogen which causes severe nosocomial infections such as meningitis. Multidrug resistance is a growing problem throughout the world. In this report a case of multidrug resistant A.baumannii meningitis, treated with high dose of ampicillin-sulbactam (SAM) was presented. Rhinorrhea and confusion developed on the postoperative seventh day in a 67 years old male patient operated for macroadenoma of the hyphophysis gland. Since the cerebrospinal fluid (CSF) findings indicated a central nervous system infection, nosocomial meningitis was diagnosed and intravenous ceftazidime and vancomycin have started. Blood and CSF cultures of the patient revealed no growth and his general condition has improved. However, fever and confusion emerged again on the 21st day of therapy and the repeat CSF sample revealed increased pressure, purulent appearance, 510/mm3 leukocytes (90% PMNL), 58 mg/dl glucose (simultaneous blood glucose was 144 mg/dl) and 49 mg/dl protein. Direct microscopic examination of CSF revealed gram-negative coccobacilli and A.baumannii was identified in the culture. The isolate was resistant to piperacillin-tazobactam, third generation cephalosporins, aztreonam, ciprofloxacin, carbapenems and aminoglycosides, susceptible to sulbactam ampicillin and colistin. Ampicillin (12 gr) and sulbactam (6 gr) treatment was initiated and at the 72nd hour of the therapy the temperature and conciousness level of the patient returned to normal. Control CSF sample obtained on the 14th day of treatment revealed no leukocytes and no bacterial growth. The treatment was continued for 21 days and the patient recovered without any sequela. Since colistin which is one of the alternative antimicrobial treatment choices for resistant Acinetobacter infections, is not found in Turkey, sulbactam-ampicillin might be an effective and safe choice for the treatment of multi-resistant A. baumannii meningitis if the isolate was proven to be susceptible by antibiotic susceptibility tests.

Anti-Bacterial Agents

therapeutic use

205134430

Antiretrovirals during pregnancy: a note of caution.

TO THE EDITOR—In their editorial about antiretrovirals in pregnancy, Watts and Mofenson note that as antiretroviral treatment (ART) is rolled out more widely for pregnant women in resource-limited settings, it will be critical to carefully monitor pregnancy outcomes, including congenital anomalies, preterm birth, stillbirth, and infant mortality, to assess risks and benefits of the different regimens [1]. Wewant to caution against another potential adverse effect of the maternal tripledrug ART regimen during pregnancy and breast-feeding (the World Health Organization’s option B strategy [2]): pregnancy-related neuropsychiatric disorders including postpartum depression (PPD). Specifically, in the option B strategy, all human immunodeficiency virus (HIV)– positive pregnant women, regardless their CD4 T-cell count, will be treated with a regimen that includes the nonnucleoside reverse-transcriptase inhibitor efavirenz. Efavirenz, however, is known to cause neuropsychiatric side effects, including anxiety and depressive symptoms [3]. In a pharmacokinetic study in Uganda, up to 69% of participants experienced adverse central nervous system symptoms attributable to efavirenz in the first 2 weeks after initiating an efavirenz-based regimen [4]. The incidence of neuropsychiatric side effects during efavirenz therapy is correlated with plasma concentrations, and African

HIV Infections

drug therapy

34367752

The role of CD24 in various human epithelial neoplasias.

CD24 is a small, heavily glycosylated glycosylphosphatidylinositol-linked cell surface protein, which is expressed in hematologic malignancies and in a large variety of solid tumors. It appears to function as a ligand of P-selectin, an adhesion molecule present in activated platelets and endothelial cells. The authors aimed at evaluating CD24 protein expression in adenoma and adenocarcinoma of the stomach, colon, gallbladder, ovary, and breast to establish a correlation with clinicopathologic data. Staining was evaluated using four degrees of positivity (negative, weakly, moderately, strongly positive), and the staining patterns (membranous vs. intracytoplasmic) were analyzed for statistical analysis. The present study clearly demonstrates that CD24 is abundantly expressed in adenocarcinoma compared to adenoma of the colon and breast. Moreover, the positivity degree of CD24 expression increases with positive nodal status in advanced gastric carcinoma. Intracytoplasmic CD24 expression was found to be highly associated with adenocarcinoma of the colon, gallbladder, and ovary compared to the adenoma group of those organs, and with the positive nodal status compared to the negative nodal status of the colonic adenocarcinoma. We conclude that the degree of positivity and the staining pattern of CD24 constitute an important molecular marker for various epithelial neoplasms, which could help to define malignant transformation and to predict lymph node metastasis.

Adenocarcinoma

metabolism

9094344

Inflammatory markers in exhaled breath condensate in patients with asthma and rhinitis.

INTRODUCTION The present study investigates the lower airway inflammation using malondialdehyde and total protein measurement in exhaled breath condensate in mild asthma, persistent rhinitis, and concomitant asthma and rhinitis. PATIENTS AND METHODS Asthmatics with mild disease, patients with persistent rhinitis symptomatic for at least one year and healthy controls were included. Asthmatics and rhinitis patients were all newly diagnosed and were free of corticosteroid therapy. Participants were nonsmokers, had no respiratoy tract infection within the previous month. Rhinitis patients with asthmatic symptoms and positive bronchial challenge were grouped as patients with persistent rhinitis and concomitant asthma. Malondialdehyde and total protein were measured in the exhaled breath condensate collected from the subjects. RESULTS No statistical difference was found in the malondialdehyde and total protein levels in exhaled breath condensate between the four study groups which are; 53 patients with persistent rhinitis, 12 with mild asthma, 16 persistent rhinitis patients with concomitant asthma and 13 healthy controls (p> 0.05). Atopy and nasal eosinophilia were not related to malondialdehyde and total protein levels in exhaled breath condensate. CONCLUSION Lower airway inflammation is not a disease specific process and is not a prerequisite concerning patients with mild asthma or rhinitis or patients with coexistence of both diseases.

Asthma

diagnosis

24839984

Cognitive Complaints in Survivors of Breast Cancer After Chemotherapy Compared With Age-Matched Controls: An Analysis From a Nationwide, Multicenter, Prospective Longitudinal Study.

Purpose Cancer-related cognitive impairment is an important problem for patients with breast cancer, yet its trajectory is not fully understood. Some previous cancer-related cognitive impairment research is limited by heterogeneous populations, small samples, lack of prechemotherapy and longitudinal assessments, use of normative data, and lack of generalizability. We addressed these limitations in a large prospective, longitudinal, nationwide study. Patients and Methods Patients with breast cancer from community oncology clinics and age-matched noncancer controls completed the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) at prechemotherapy and postchemotherapy and at a 6-month follow-up as an a priori exploratory aim. Longitudinal models compared FACT-Cog scores between patients and controls at the three assessments and adjusted for age, education, race, menopausal status, and baseline reading ability, anxiety, and depressive symptoms. A minimal clinically important difference cutoff determined percentages of impairment over time. Results Of patients, 581 patients with breast cancer (mean age, 53 years; 48% anthracycline-based regimens) and 364 controls (mean age, 53 years) were assessed. Patients reported significantly greater cognitive difficulties on the FACT-Cog total score and four subscales from prechemotherapy to postchemotherapy compared with controls as well as from prechemotherapy to 6-month follow-up (all P < .001). Increased baseline anxiety, depression, and decreased cognitive reserve were significantly associated with lower FACT-Cog total scores. Treatment regimen, hormone, or radiation therapy was not significantly associated with FACT-Cog total scores in patients from postchemotherapy to 6-month follow-up. Patients were more likely to report a clinically significant decline in self-reported cognitive function than were controls from prechemotherapy to postchemotherapy (45.2% v 10.4%) and from prechemotherapy to 6-month follow-up (36.5% v 13.6%). Conclusion Patients with breast cancer who were treated in community oncology clinics report substantially more cognitive difficulties up to 6 months after treatment with chemotherapy than do age-matched noncancer controls.

Breast Neoplasms

drug therapy

43151953

Toxicity and outcomes in combined modality treatment of head and neck squamous cell carcinoma: cisplatin versus cetuximab.

AIMS The standard of care for locally advanced head and neck squamous cell carcinoma (HNSCC) is radiation therapy (RT) with concurrent cisplatin (CIS). Patients with renal or cardiac dysfunction, hearing loss or poor performance status (PS) may receive RT and cetuximab (CET) at our institution. This study compares treatment toxicities and outcomes. METHODS AND MATERIALS All patients treated with curative intent RT and concurrent CIS (100 mg/m 2 Day 1, 22, 43) or CET (400 mg/m 2 Day -7, 250 mg/m 2 weekly during RT) between August 2007 and July 2010 were reviewed and toxicity and outcomes analyzed. RESULTS Among 349 subjects (262 RT-CIS, 87 RT-CET) characteristics were similar except in age, head and neck subsite and RT fractionation. RT-CIS required more dose reductions, delays, and unplanned admissions and received less intended systemic therapy (ST). Weight loss and gastrostomy-tube use were similar. RT-CIS caused more nausea/vomiting, while RT-CET was associated with more dermatitis and acneiform rash. With mean follow-up of 20 months and 16 months, RT-CIS subjects experienced improved 1-year locoregional control (LRC) (90% vs. 72%, P < 0.01), disease-free survival (DFS) (83% vs. 67%, P < 0.01) and overall survival (OS) (90% vs. 80%, P = 0.04). On multivariate analysis type of ST was associated with LRC and DFS, but not OS. CONCLUSIONS In patients with locally advanced HNSCC, CIS and CET were associated with different toxicity profiles. RT-CIS was associated with improved LRC and DFS, but similar OS compared to RT-CET.

Antineoplastic Agents

therapeutic use

37553768

In vivo and in vitro effects of methylmercury on the activities of aminoacyl-tRNA synthetases in rat brain

The activities of six aminoacyl-tRNA synthetase species were determined using enzyme preparations partially purified from the brains of control and methylmercury (MeHg)-treated rats. The activities of Asp-, Leu- and Tyr-tRNA synthetases were significantly reduced in the brains of MeHg-intoxicated rats, whereas those of Lysand Met-tRNA synthetases remained unchanged. In contrast, the activity of His-tRNA synthetase was significantly increased in the symptomatic phase of MeHg intoxication. The activities of these six aminoacyl-tRNA synthetases in the control brains were affected to different extents on the direct addition of MeHg to the assay system in vitro. No positive correlation was observed between the in vivo and in vitro effects of MeHg on the enzyme activities. These results indicate that the aminoacylation of tRNA is one of the actions of MeHg, which leads to inhibition of protein synthesis, and it is suggested that the syntheses of cellular proteins may be modified in different ways by MeHg, depending on their amino acid compositions.

Brain

enzymology

39908076

Biochemical and immunological studies on isolated brush border membranes of human kidney cortex and their membrane surface proteins.

Abstract A subfraction rich in brush border (BB) membranes was obtained by differential centrifugation of plasme membranes (PM) of human kidney cortex. In addition to alkaline phosphatase, the usual BB marker enzyme, an alanine specific aminopeptidase (AAP) and a gamma-glutamyltranspeptidase (g-GTP) were associated with this membrane fraction. The three enzymes are considered specific markers for the brush border region of the proximal tubules. Among the proteins released from the BB membranes by proteolytic treatment these three enzymes were found. The results indicate that AAP and g-GTP are components of the outer membrane surface. Antisera prepared against PM reacted in several immunological techniques with soluble proteins (including the three BB marker enzymes) released from the BB membranes by digestion with papain, as well as with those found in the urine of patients with kidney diseases. AAP from both sources (papain digest and urine) were immunologically indistinguishable. The molecular weights and some other biochemical parameters of the three enzymes were determined and compared with those reported in the literature. It is suggested that the methods and systems described might be of use for further studies on the structure and function of the membranes of kidney proximal tubules and are of potential value for diagnostic purposes.

Proteins

analysis

40882079

Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes.

BACKGROUND Resistin is a recently identified adipocyte-secreted hormone in rodents, and has been proposed to serve as a link between obesity and insulin resistance. The aim of this study was to develop a sensitive enzyme-linked immunosorbent assay (ELISA) for human resistin and evaluate serum resistin concentrations in normal subjects and patients with type 2 diabetes. METHODS Using ELISA developed by two polyclonal antibodies, resistin concentrations were measured in 90 patients with type 2 diabetes and compared to 74 healthy control subjects. RESULTS This ELISA has high specificity and sensitivity over the concentration of range 0.5-100 ng/ml with good percentage recovery (97.1 +/- 4.7%) and reproducibility (within-day assay, CV = 4.8-8.6%; between-day assay, CV = 5.6-9.7%). The mean concentration of resistin in sera from type 2 diabetic patients was significantly higher than that in normal subjects (mean +/- S.E.: 20.8 +/- 0.7 vs. 14.9 +/- 0.5 ng/ml, p < 0.001). A moderate positive correlation was observed between serum resistin levels and body mass indices in both normal subjects (r = 0.412, p < 0.0003) and patients with type 2 diabetes (r = 0.395, p < 0.0001). CONCLUSIONS Our ELISA will be useful to confirm the physiological and pathophysiological role of resistin in humans.

Diabetes Mellitus, Type 2

blood

16608244

Strategies for the identification of novel brain specific genes affected in Alzheimer disease.

The pathological changes that occur in Alzheimer disease (AD) brain lead to a large loss of various classes of neurons and the production of novel proteinaceous elements such as neuritic plaques and neurofibrillary tangles. For the neuronal loss to occur and these elements to arise, there must be a disturbance in the expression or regulation of genes that code for proteins required for normal cell maintenance, or perhaps even for the expression of genes unique to AD. We describe the construction of a cDNA library from the human substantia innominata and strategies for isolating genes that are expressed differentially between brain regions and which may be affected by AD. Some of the results obtained using these strategies and a preliminary description of a novel brain specific mRNA of 15.5kb, whose expression is increased in AD affected temporal cortex, are presented.

Brain

metabolism

24642515

Site-specific attachment of functionalized poly(ethylene glycol) to the amino terminus of proteins.

A convenient method for the construction of site-specifically modified poly(ethylene glycol)-protein conjugates is described. This method relies on the ability to generate a reactive carbonyl group in place of the terminal amino group. If the protein has N-terminal serine or threonine, this can be done by very mild periodate oxidation and generates a glyoxylyl group. A method less restricted by the nature of the N-terminal residue, but which requires somewhat harsher conditions, is metal-catalyzed transamination, which gives a keto group. The N-terminal-introduced reactive carbonyl group specifically reacts, under mild acidic conditions, with an aminooxy-functionalized poly(ethylene glycol) to form a stable oxime bond. Using polymers of different size and shape (linear or multibranched), various conjugates of IL-8, G-CSF, and IL-1ra were constructed and further characterized with respect to their biological activity and pharmacokinetic behavior in rats. Unlike most previous methods, this approach places a single PEG chain at a defined site on the protein. It should therefore be more likely to conserve biological activity when the latter depends on interaction with another macromolecule (unlike enzymic activity which often survives multiple PEGylation).

Proteins

chemistry

30749514

A correlation analysis of protein characteristics associated with genome-wide high throughput expression and solubility of Streptococcus pneumoniae proteins.

We have developed and evaluated a highly parallel protein expression and purification system using ORFs derived from the pathogenic bacterium Streptococcus pneumoniae as a representative test case in conjunction with the Gateway cloning technology. Establishing high throughput protein production capability is essential for genome-wide characterization of protein function. In this study, we focused on protein expression and purification outcomes generated from an expression vector which encodes an NH(2)-terminal hexa-histidine tag and a COOH-terminal S-tag. Purified recombinant proteins were validated by SDS-PAGE, followed by in-gel digestion and identification by MALDI-TOF/TOF analysis. Starting with 1360 sequence-validated destination clones we examined correlation analyses of expression and solubility of a wide variety of recombinant proteins. In total, 428 purified proteins (31%) were recovered in soluble form. We describe a semi-quantitative scoring method using an S-tag assay to improve the throughput and efficiency of expression and solubility studies for recombinant proteins. Given a relatively large dataset derived from proteins representing all functional groups in a microbial genome we correlated various protein characteristics as they relate to protein expression outcomes.

Bacterial Proteins

metabolism

20143202

A survey of practice in management of malignant ascites.

The purpose of this study was to determine physicians' attitudes toward and preferences for palliative management of malignant ascites. A random sample of eighty physicians practicing in Canada was selected from the memberships of the Canadian Association of Medical Oncologists, the Canadian Association of Gastroenterology, the Canadian Society of Palliative Care Physicians, and the Society of Gynecologic Oncologists of Canada. Physicians were questioned on their use of different modalities in management of malignant ascites, and preferences based on attitudes toward efficacy of various treatments. Eighty surveys were mailed, with a second mailing, followed by telephone contact. The response rate was 76% (59/78), with two potential respondents deemed ineligible. Among the 44 physicians who treat malignant ascites, paracentesis is employed by 43 (98%), and felt to be effective by 39 (89%). Diuretics are used by 61% (27/44), although fewer feel diuretics are effective management (20/44, 45%). Peritoneovenous shunts, dietary measures, and other modalities are used less frequently than either paracentesis or diuretics. The most commonly used means of managing malignant ascites is paracentesis, which is also felt to be the most effective by the group surveyed. After paracentesis, diuretics and peritoneovenous shunting are used most frequently, but there is no apparent consensus as to their effectiveness. Managing malignant ascites remains problematic, and we propose further study of management strategies to clarify the role of various treatments.

Neoplasms

complications