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35959927

WGS analysis and molecular resistance mechanisms of azithromycin-resistant (MIC >2 mg/L) Neisseria gonorrhoeae isolates in Europe from 2009 to 2014.

OBJECTIVES To elucidate the genome-based epidemiology and phylogenomics of azithromycin-resistant (MIC >2 mg/L) Neisseria gonorrhoeae strains collected in 2009-14 in Europe and clarify the azithromycin resistance mechanisms. METHODS Seventy-five azithromycin-resistant (MIC 4 to >256 mg/L) N. gonorrhoeae isolates collected in 17 European countries during 2009-14 were examined using antimicrobial susceptibility testing and WGS. RESULTS Thirty-six N. gonorrhoeae multi-antigen sequence typing STs and five phylogenomic clades, including 4-22 isolates from several countries per clade, were identified. The azithromycin target mutation A2059G (Escherichia coli numbering) was found in all four alleles of the 23S rRNA gene in all isolates with high-level azithromycin resistance (n = 4; MIC ≥256 mg/L). The C2611T mutation was identified in two to four alleles of the 23S rRNA gene in the remaining 71 isolates. Mutations in mtrR and its promoter were identified in 43 isolates, comprising isolates within the whole azithromycin MIC range. No mutations associated with azithromycin resistance were found in the rplD gene or the rplV gene and none of the macrolide resistance-associated genes [mef(A/E), ere(A), ere(B), erm(A), erm(B), erm(C) and erm(F)] were identified in any isolate. CONCLUSIONS Clonal spread of relatively few N. gonorrhoeae strains accounts for the majority of the azithromycin resistance (MIC >2 mg/L) in Europe. The four isolates with high-level resistance to azithromycin (MIC ≥256 mg/L) were widely separated in the phylogenomic tree and did not belong to any of the main clades. The main azithromycin resistance mechanisms were the A2059G mutation (high-level resistance) and the C2611T mutation (low- and moderate-level resistance) in the 23S rRNA gene.

Anti-Bacterial Agents

pharmacology

5014899

SPRINT Proves that Lower Is Better for Nondiabetic High-Risk Patients, but at a Price.

SPRINT was a well designed and executed randomized clinical trial funded by the National Institutes of Health (NIH) in which 9,361 hypertensive patients at high risk of cardiovascular disease with blood pressure (BP) above 130 mm H g and below 180 mm H g, were randomly assigned to be treated to a goal systolic BP (SBP) of less than 140 vs. less than 120 mm Hg. The trial recruited hypertensive individuals in the United States who were older than 50 years of age and had never had a stroke and were not diabetic, but were either older than 75 years of age (28% of subjects), had chronic kidney disease with estimated glomerular filtration rate (eGFR) 20 m l/min/1.73 m 2 of body surface (28% of subjects), or had clinical or subclinical cardiovascular disease or a Framingham score indicating 10-year risk of >15% of cardiovascular disease. By 1-year post-randomization, the trial achieved SBPs of 121.4 mm H g in the intensive treatment group and 136.2 mm H g in the standard treatment group, a difference that was maintained throughout the trial. SPRINT was stopped early after a median follow-up of 3.26 years because of a 25% relative risk reduction in the intensive treatment group of the primary endpoint (myocardial infarction or other coronary syndromes, stroke, heart failure, or death from cardiovascular causes) and 27% in all-cause mortality. In order to achieve these results, patients in the intensive therapy group took a mean of approximately 3 vs. 2 antihypertensive drugs in the standard therapy group. About 3,000 patients in each group completed 3 years of the trial, a little more than 1,000 completed 4 and slightly less than 300 in each group completed 5 years of the trial. The beneficial results were found across all prespecified groups. However, it is noteworthy that individuals older than 75 years of age appeared to benefit more than younger subjects. Is it possible that these older individuals were “survivors,” who although at high cardiovascular risk, were able to benefit more than the more “mixed” younger group? As well, those subjects who entered the trial with SBP of <132 mm H g also benefited more than those who entered the trial with higher SBP, both in terms of relative and absolute risk reduction. The protocol required that individuals assigned to the standard therapy group who entered with lower BP than goal have their antihypertensive medication down-titrated. 2 In contrast, those assigned to the intensive therapy group would be up-titrated. No specific drug algorithm was used and the broad range of antihypertensive drugs utilized were provided to participants free of charge. Since among secondary endpoints 2 were highly significant in favor of the intensive therapy group, heart failure, and death from cardiovascular disease, as well as all-cause mortality, is it possible that in a high-risk population down-titration of medication, perhaps renin–angiotensin inhibitors, vs. use of a high dose of these in the intensive therapy group, progressively uncovered latent heart failure contributing to the results observed? The rise in BP after down-titration may also have contributed to the higher event rates for these conditions. Importantly, serious adverse effects deemed related to treatment were twice as frequent in the intensive therapy group than in the standard therapy group, and although not trivial and some

Hypertension

therapy

175151

[Transmural and nontransmural myocardial infarction. Clinical course and prognosis (author's transl)].

In a group of 701 patients with acute myocardial infarction treated in the intensive care unit from 1969 to 1976 557 ((79,5%) had a transmural infarction. The clinical course in these patients was significantly more aggravated by haemodynamic complications especially left and right heart failure and cardiogenic shock. The pericarditis appeared with an incidence of 10,4% as complication of transmural myocardial infarction only. Atrioventricular block, supraventricular ectopies, ventricular fibrillation and intraventricular disturbance of conduction occurred more frequently in patients with transmural myocardial infarction. Corresponding to the larger size of infarction the maximal average rise of serum enzymes (SGOT, CPK) was observed in this group. The hospital mortality was 28,2%, compared to 11,2% of the patients with nontransmural infarction.

Myocardial Infarction

diagnosis

29268492

Interaction between a cationic porphyrin and ctDNA investigated by SPR, CV and UV-vis spectroscopy.

The interaction between ctDNA and a cationic porphyrin was studied in this work. The binding process was monitored by surface plasmon resonance (SPR) spectroscopy in detail. The association, dissociation rate constants and the binding constants calculated by global analysis were 2.4×10(2)±26.4M(-1)s(-1), 0.011±0.0000056s(-1) and 2.18×10(4)M(-1), respectively. And the results were confirmed by cyclic voltammetry and UV-vis absorption spectroscopy. The binding constants obtained from cyclic voltammetry and UV-vis absorption spectroscopy were 8.28×10(4)M(-1) and 6.73×10(4)M(-1) at 298K, respectively. The covalent immobilization methodology of ctDNA onto gold surface modified with three different compounds was also investigated by SPR. These compounds all contain sulfydryl but with different terminated functional groups. The results indicated that the 11-MUA (HS(CH2)10COOH)-modified gold film is more suitable for studying the DNA-drug interaction.

DNA

chemistry

22874060

[The influence of side-to-side portacaval shunt plus enhancement of perfusion of hepatic artery on cirrhotic liver: an experimental study].

OBJECTIVE To for improving the perfusion of liver, we designed an operation of portacaval shunt (PCS) plus enhancement of perfusion of hepatic artery (EPHA). METHOD 48 wistar rats were divided into 4 groups randomly. group I (normal control), group II (liver cirrhotic control), group III (PCS on liver cirrhosis), and group IV (PCS + EPHA on liver cirrhosis). The EPHA was performed by the ligation of the left gastric and splenic artery. Liver function tests, liver biopsy, and nuclide hepatobiliary dynamic imaging (NHDI) were performed on the 2nd week and the 6th month after operation. RESULT In NHDI, the peak time was short (P < 0.05) and the excretive rate was high (P < 0.01). The liver function and the proliferative degree of the fibrotic tissue of the liver were perfected significantly (P < 0.05) in the group IV compared with the group III after operation. CONCLUSION PCS + EPHA can increase the perfusion of the hepatic artery, maintain the liver function and delay liver cirrhosis, and overcome the side effects of PCS. It is a new surgical technique in treating portal hypertension.

Liver

blood supply

25912950

Clinical course of cardiovascular involvement in the mucocutaneous lymph node syndrome. Relation between clinical signs of carditis and development of coronary arterial aneurysm.

Seventy-nine patients with mucocutaneous lymph node syndrome were evaluated prospectively by clinical examination, electrocardiography, chest radiography, M mode and two dimensional echocardiography and thallium-201 myocardial scanning. Serial changes were categorized according to the duration of illness: stage I (1 to 10 days), stage II (11 to 20 days), stage III (21 to 30 days), stage IV (31 to 60 days) and stage V (61 days to 40 months). The presence of myocarditis in stages I and II was suggested in 40 of 79 patients (50.6 percent) by electrocardiographic, echocardiographic, radiographic and clinical abnormalities. Myocarditis was accompanied by pericarditis in six patients and by both endocarditis and pericarditis in one patient. These signs of inflammation were resolved by stage III in all but three patients with electrocardiographic abnormalities. In the active stage, large coronary arterial lesions were suspected only because of an abnormal spherical echo-free space in the region of the coronary arteries on two dimensional echocardiograph as well as electrocardiographic evidence of deep Q waves in leads II, III and aVF. One or more coronary aneurysms developed in 11 patients, primarily in stage II; regression of the aneurysm was noted in 5 of these patients during stages III, IV and V. Aneurysm regression demonstrated by angiography did not correlate with echocardiographic changes in aneurysm size in one patient. Moreover, the occurrence of coronary aneurysm did not correlate with the presence of signs of carditis, because the frequency of carditis was the same in patients with and without aneurysm.

Cardiovascular Diseases

diagnosis

1460660

Expression of Phosphorylated Histone H2AX (&ggr;-H2AX) in Normal and Neoplastic Squamous Epithelia of the Uterine Cervix: An Immunohistochemical Study With Epidermal Growth Factor Receptor

The histone &ggr;-H2AX is a marker of activated DNA damage and is overexpressed in different cancers and their precursor lesions, indicating a role in oncogenic transformation. Epidermal growth factor receptor (EGFR) is overexpressed in many kinds of epithelial neoplasms. This study aimed to determine whether immunohistochemical expression of &ggr;-H2AX is involved in the progression of the morphological spectrum from normal squamous cervical epithelia (NE, n=33) to cervical intraepithelial neoplasia (CIN; CIN1, n=9; CIN2/3, n=33) and cervical invasive squamous cell carcinoma (ISCC, n=33), whether &ggr;-H2AX expression follows the pattern of proliferation of atypical squamous cells as shown by EGFR immunoreactivity, and whether it is correlated with clinicopathologic variables in ISCC. Immunostaining for both the factors was scored semiquantitatively for moderate and strong intensities. Gamma-H2AX and EGFR expression, respectively, increased from NE and CIN1 to CIN2/3 and ISCCs significantly (P=0.0001, respectively). Gamma-H2AX reactivity was found in the nuclei of the cells of the upper epithelial levels and the cells of basal/parabasal type in variable quantities in NE and CIN; expression of &ggr;-H2AX was seen in the nuclei of ISCC including keratinizing cells in horn pearls. EGFR staining was mainly membranous and noted in basal/parabasal cells in NE and atypically proliferating keratinocytes in CIN and nonkeratinizing cells of ISCC. In addition, immature squamous metaplasias were decorated by the antibodies used. Immunoscores for &ggr;-H2AX and EGFR, respectively, did not differ between International Federation of Gynecology and Obstetrics stages I and II, keratinizing and nonkeratinizing ISCC, and CIN2/3 and ISCC. However, expression patterns were different for both the factors, suggesting their involvement in different biological mechanisms, with regard to &ggr;-H2AX apart from proliferation. Overexpression of &ggr;-H2AX in CIN2/3 and ISCC of the uterine cervix reflects the neoplastic transformation of cervical squamous epithelia in reaction to increased DNA-damage and supports the classification of dysplasia into low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions.

Carcinoma, Squamous Cell

metabolism

32225556

Draft Genome of a Brazilian Avian-Pathogenic Escherichia coli Strain and In Silico Characterization of Virulence-Related Genes

ABSTRACT Avian-pathogenic Escherichia coli (APEC) strains cause extraintestinal diseases in avian species. Here, we present the draft genome of an APEC strain (SCI-07) from Brazil that was isolated from skin lesions (gelatinous edema) on the head and periorbital tissues of a laying hen with swollen head syndrome.

Escherichia coli

genetics

19682799

Easy construction of an improved fine wire electrode for chronic single neuron recording in freely moving animals

An easy and improved method for construction and implantation of fine wire electrodes is described. These electrodes have been found to be effective in long-term recording of single unit activity in freely behaving and ingesting animals when chronically implanted in any region of the brain in rats.

Brain

physiology

10523398

Morphologic, biochemical, and molecular evidence of apoptosis during the reperfusion phase after brief periods of renal ischemia.

A multiparametric analysis to demonstrate that even brief periods of arterial clamping can initiate extensive cell loss in a rat kidney through the process of apoptosis during the 48-hour period after reperfusion was performed. Microscopic examination of rat renal tissues subject to a 5-, 30-, or 45-minute period of complete ischemia showed the presence of apoptotic bodies both within and occasionally between renal tubules, appearing as early 12 hours after reperfusion, and increasing in numbers at 24 hours. Furthermore, DNA extracted from such reperfused renal tissue demonstrated the appearance of a distinct "ladder" pattern of DNA fragments after electrophoresis in agarose gels, a phenomenon commonly associated with cells undergoing apoptosis and in contrast to the predominant smear pattern obtained after electrophoresis of DNA extracted from necrotic renal tissue. Finally, messenger RNA (mRNA) encoding sulfated glycoprotein-2, a gene product previously identified to apoptotic renal cells, was found to be highly expressed in the 30-minute arterial clamped rat kidney after 24 hours of reperfusion, but was not detectable in mRNA extracted from renal tissue after 24 hours chronic infarction. This study demonstrates that a combination of morphologic, biochemical, and molecular markers can be used to distinguish predominant modes of cell death in varying forms of tissue injury. Application of these analytical techniques to renal vascular injury has distinguished that brief periods of complete ischemia initiates a form of cell death (apoptosis) during a subsequent reperfusion phase that is drastically different from cellular necrosis induced by prolonged severe ischemia.

Kidney

pathology

24576385

Impact of type 2 diabetes mellitus on diffuse inflammatory activation of de novo atheromatous lesions: implications for systemic inflammation.

AIMS Local coronary and systemic inflammation is pronounced in patients with diabetes mellitus (DM). Intracoronary thermography detects local inflammation and C-reactive protein (CRP) is a marker of systemic inflammation. We investigated whether or not, in patients with DM, thermal heterogeneity of culprit lesions (CLs) correlates with that of non-culprit lesions (NCLs) and with systemic inflammation. METHODS We included DM patients who had two angiographically significant lesions and were undergoing percutaneous coronary intervention. We measured the temperature difference (DeltaT) between the lesion and proximal vessel wall. RESULTS We included 104 (n=208 lesions) patients: 32 (n=64 lesions) had DM and 72 (n=144 lesions) were non-DM (control group). DeltaT was increased in DM in both CLs and NCLs (CLs: DM=0.12+/-0.06 degrees C; no DM=0.06+/-0.04 degrees C; P<0.01 versus NCLs: DM=0.13+/-0.08 degrees C versus no DM=0.06+/-0.05 degrees C; P<0.01). Patients with DM had similar DeltaT in CLs and NCLs (P=0.49). A linear correlation was detected between heat production in all lesions and CRP (R=0.45; P<0.01), which was attributed to the correlation of DeltaT in lesions of patients with DM and CRP (R=0.32; P<0.01). In lesions of patients with low CRP, a greater rate of discrepancy was found, as 100% of lesions in patients with DM versus 66.1% of lesions of patients without DM had a high DeltaT in one or both lesions (P<0.01). CONCLUSION In patients with DM, local inflammatory activation is diffuse and correlates with systemic inflammation. However, low systemic inflammatory activation does not always predict an increase in local thermal heterogeneity.

Diabetes Mellitus, Type 2

physiopathology

42095755

Stereochemical analysis of hydroxylated docosahexaenoates produced by human platelets and rat brain homogenate.

The stereochemical configuration of hydroxylated products of docosahexaenoic acid (22:6w3) formed by human platelets and rat brain homogenate were characterized for the first time. Chiral phase HPLC was employed along with autooxidized 22:6w3 as reference material. The 14- and 11-hydroxy 22:6w3 (HDHE) products produced by human platelets were in the S configuration. Rat brain homogenate produced all of the ten possible positional isomers when incubated with 22:6w3. Their retention behavior on the reversed and chiral phase HPLC columns and GC/MS/EI analysis indicated that they were 20-, 17-, 16-, 14-, 13-, 11-, 10-, 8-, 7- and 4-HDHE. However, stereochemical analysis revealed that each positional isomer was a racemic mixture, suggesting that these were not formed by lipoxygenation but mainly by peroxidation process.

Brain

metabolism

6717982

Measuring the wisdom of the crowds in network-based gene function inference

MOTIVATION Network-based gene function inference methods have proliferated in recent years, but measurable progress remains elusive. We wished to better explore performance trends by controlling data and algorithm implementation, with a particular focus on the performance of aggregate predictions. RESULTS Hypothesizing that popular methods would perform well without hand-tuning, we used well-characterized algorithms to produce verifiably 'untweaked' results. We find that most state-of-the-art machine learning methods obtain 'gold standard' performance as measured in critical assessments in defined tasks. Across a broad range of tests, we see close alignment in algorithm performances after controlling for the underlying data being used. We find that algorithm aggregation provides only modest benefits, with a 17% increase in area under the ROC (AUROC) above the mean AUROC. In contrast, data aggregation gains are enormous with an 88% improvement in mean AUROC. Altogether, we find substantial evidence to support the view that additional algorithm development has little to offer for gene function prediction. AVAILABILITY AND IMPLEMENTATION The supplementary information contains a description of the algorithms, the network data parsed from different biological data resources and a guide to the source code (available at: http://gillislab.cshl.edu/supplements/).

Proteins

metabolism

9224429

Depression and older people: securing wellbeing in later life.

This article, brought to you in association with Help the Aged, looks at the factors that can contribute to depression in older people and highlights the information available from the Charity.

Aging

psychology

33414372

Prediction of ruminal volatile fatty acids and pH within the net carbohydrate and protein system.

A steady-state model of the production, absorption, passage, and concentration of ruminal VFA and pH is developed from published literature data and is structured to use the feed descriptions and inputs from the net carbohydrate and protein system. Included are the effects of pH on growth rate and yield of structural and non-structural carbohydrate-fermenting bacteria; production of acetate, propionate, butyrate, lactate, and methane; conversion of lactate to VFA; ruminal absorption of acids; and prediction of ruminal pH from dietary measures and from ruminal buffering and acidity. The root mean square error of predicted total VFA concentration was 12 mM. Individual VFA fractions were inadequately predicted. In a review of literature data, effective NDF (eNDF) provided a better correlation with ruminal pH than forage or NDF. Digestion rate of NDF remained at normal levels above pH 6.2, which corresponds to a minimum eNDF of 20% of dietary DM. Further research is needed to determine the individual VFA produced from carbohydrate fractions at various pH, the appropriateness of partitioning the starch and pectin carbohydrate pool into slowly and rapidly degraded fractions, and the effect on microbial yield, total tract digestibility, and predicted energy values of feeds.

Proteins

metabolism

20203624

[Pathology and significance of leptin resistance in obesity].

Leptin, the protein product of the ob gene, is predominantly secreted from white adipose tissue, and acts on the brain to regulate food intake, energy expenditure, and neuroendocrine function. Obese rodent and humans are mostly associated with high circulating leptin levels. These findings have led to the conclusion that obese individuals are relatively insensitive to endogenous leptin termed 'leptin resistance'. The potential sites for leptin resistance include the blood-brain-barrier transport system and the leptin signaling mechanism in leptin-responsive neurons in the hypothalamus. In this review, we describe leptin, leptin receptor, and potential hypothesis of leptin resistance.

Obesity

physiopathology

221334099

Clinicopathological features of superficial spreading and nonspreading squamous cell carcinoma of the esophagus

Abstract OBJECTIVES: Superficially spreading carcinoma of the esophagus, consisting mainly of intraepithelial carcinoma, is not as rare as was previously thought. Despite the surgical significance of this entity, no general definition has been established, and the clinical features of this disease remain to be clarified. METHODS: A total of 54 patients with superficial carcinoma of the esophagus (defined as carcinoma limited to the epithelium or superficially invading the lamina propria or submucosa) were classified into two groups according to the longitudinal extent of the lesion. A total of 13 patients with superficially spreading carcinoma (defined as a superficial carcinoma measuring >5 cm and consisting mainly of intraepithelial carcinoma) were compared to 41 patients with nonspreading esophageal carcinoma. RESULTS: One patient with superficially spreading carcinoma had a positive resection margin because of multiple cancerous lesions. The only significant difference in the clinical and pathological features of the two groups was a higher prevalence of associated multiple cancerous lesions in patients with the superficially spreading type. CONCLUSIONS: Superficially spreading carcinoma of the esophagus is often associated with multiple cancerous lesions. For endoscopists and esophageal surgeons, it is important to define the proximal extent of intraepithelial cancer and the presence of multiple cancerous lesions to perform curative resection.

Carcinoma, Squamous Cell

pathology

35623597

Awareness of STDs and HIV/AIDS among the adolescent girls of classes IX-XII in Amritsar, Punjab: an interventional study.

high usage of topical traditional herbal medications in Sarawak. These agents were the culprit in 71.2% (n = 42) of cases. Eczematous changes were seen in 55.9% (n = 33) of drug-related dermatoses. Psoriasiform changes were seen in 18.6%, (n = 11), vasculitic in 13.6% (n = 8), lichenoid in 5.1% (n = 3), erythema multiforme in 5.1% (n = 3) and fixed drug eruption in 1.7% (n = 1). Other studies found morbilliform rash constituting majority of cases clinicopathologically. [2,3] This is in marked contrast with the current study where eczematous changes were the commonest drug-related dermatoses because maculopapular morbilliform rashes due to drugs are not biopsied in Sarawak.

HIV Infections

prevention & control

207589960

Anti-NMDA receptor encephalitis suspected as cause of drug-induced psychosis.

To the Editor: Anti-NMDA receptor (NMDAR) encephalitis is a severe and considerably underdiagnosed form of limbic encephalopathy, with a characteristic clinical picture including psychiatric symptoms, decreased level of consciousness, hypoventilation, epileptic seizures, autonomic dysfunction, and dyskinesias. the condition is associated with autoantibodies directed against the nr1 subunit of the NMDA receptor. It was initially described in young women with ovarian teratomas, but is also common in men and children, and in the absence of neoplasms.

Mental Disorders

physiopathology

19329636

The use of horseshoe kidneys for transplantation.

Report of a case in which a horseshoe kidney was divided and transplanted into two recipients. The literature on transplantation of horseshoe kidneys is reviewed. This renal anomaly is not a contra-indication to its use for transplantation.

Kidney

abnormalities

7409496

A co-clinical platform to accelerate cancer treatment optimization.

Sophistication in DNA and RNA sequencing technology is unraveling the tremendous genetic and molecular complexity of human cancer. However, the rate at which this knowledge is being translated into patient care is too slow. To this end, we have designed and implemented a new translational platform, 'The Co-Clinical Trial Project', where data obtained in genetically engineered mouse models (GEMMs) of human cancer treated with protocols identical to those of ongoing clinical trials or with therapies already established in patients serve to rapidly: (i) stratify patients in terms of response and resistance on the basis of genetic and molecular criteria; (ii) identify mechanisms responsible for tumor resistance; and (iii) evaluate the effectiveness of drug combinations to overcome such resistance based on mechanistic understanding.

Neoplasms

therapy

32088428

Medical treatment to prevent recurrent calcium urolithiasis. A guide to critical appraisal.

Among patients with urolithiasis, the recurrence rate is 10-23% per year. We have applied guidelines for critical appraisal to 46 publications addressing the efficacy of thiazides, orthophosphates, cellulose phosphate, allopurinol, magnesium and citrate as prophylaxis against recurrent urolithiasis. The 34 studies which do not have a randomly allocated control group are subject to methodologic deficiencies such as co-intervention, variable outcome measures, variable natural history, statistical regression to the mean, selection bias and incomplete follow-up of patients. These deficiencies make conclusions regarding the efficacy of an intervention suspect. Among the 12 randomized clinical trials are 5 thiazide, 2 orthophosphate, 4 allopurinol and 1 magnesium intervention. The methodologic and statistical questions addressed were: adequacy of randomization, clinical relevance of outcomes, description of patients, clinical and statistical significance, and completeness of follow-up. Based on these methodologic considerations, one could not conclude that orthophosphates, cellulose phosphate, magnesium or citrate were efficacious in preventing recurrent urolithiasis. Two of the 5 thiazide and 1 of the 4 allopurinol randomized clinical trials demonstrate convincing evidence for efficacy of these interventions. With the exception of pilot studies of new interventions, conclusions about efficacy of interventions claimed to decrease the urolithiasis recurrence rate should be based on methodologically sound randomized clinical trials.

Calcium

analysis

73462891

High-throughput screen for sorting cells capable of producing the biofuel feedstock botryococcene.

Botryococcene is a branched triterpene produced by the algae Botryococcus braunii. Hydrocracking botryococcene yields a variety of combustible fuels such as gasoline and jet fuel. Engineering host systems and proteins involved in the biosynthesis of botryococcene to optimize production is of interest given these applications. The current study investigates the use of a diaryltetrazole based screen that undergoes a photoclick reaction with terminal alkenes, such as the branched terminal alkene present on botryococcene, to yield a fluorescent product. Host E. coli systems were established to produce botryococcene, squalene, and no triterpene to serve as a control. Cells were incubated with tetrazole and briefly irradiated with UV light to initiate the photoclick reaction. It was found that the botryococcene producing cells yielded observable fluorescence while the squalene and control cells had negligible fluorescence turn-on activity. Fluorescence-activated cell sorting (FACS) was subsequently used to identify and sort botryococcene producing E. coli from a mixture of control and squalene producing cells.

Escherichia coli

metabolism

24098953

Staged Sequential Reconstruction of a Total Lower Lip, Chin, and Anterior Mandibular Defect

The combination of a total lower lip, chin, and anterior mandibular defect following cancer resection is an extremely complex problem that requires a sequence of operations to optimize functional and aesthetic results. One patient is presented in whom the defect was reconstructed with a free fibular flap followed by a series of ancillary procedures using both modem and traditional techniques. At the time of tumor ablation, the through-and-through oromandibular defect was reconstructed with a fibular osteocutaneous flap. The lower lip and gingivolabial sulcus was reconstructed later with a tongue flap. Tissue expansion was subsequently used to replace the fibular skin with expanded submental hair-bearing skin. A polyethylene implant was added later to the fibular bone for chin augmentation. Subsequently the lower lip was supported with a tendinous graft suspended to the anterior masseter bilaterally. Lastly, the vermilion border was elevated by removing a rim of the tongue flap and covering the secondary wound with a full-thickness skin graft. At the end of the reconstructive procedures, lip seal and oral aperture were good with no drooling and excellent speech.

Carcinoma, Squamous Cell

surgery

207336092

FoxOs: Unifying Links Between Oxidative Stress and Skeletal Homeostasis

Several mechanisms contribute to the decline of all physiologic functions during aging. As a consequence, disease incidence increases with age. Central to this multifactorial process is the increase in oxidative stress levels, which correlates with age-related disease pathogenesis in animal models and in humans. Accordingly, skeletal aging and aging-related bone diseases are also associated with accumulation of reactive oxygen species. In a variety of organs, including the skeleton, mutations in components of antioxidant defense pathways have been found to lead to progressive degenerative diseases. The molecules involved are highly conserved, can sense and respond to increases in oxidative stress levels, alterations in energy status, DNA and protein damage, and they all have a common transcriptional target, the FoxO family of Forkhead transcription factors. Oxidative stress promotes both the transcriptional activity and protein stability of FoxOs. In turn, activated FoxOs promote antioxidant defense by controlling the expression of genes involved in the oxidative stress response, DNA repair, cell cycle, and apoptosis. Among the FoxO isoforms, FoxO1 in osteoblasts uses a previously unrecognized mechanism to preserve redox balance by promoting protein synthesis and subsequently inhibiting cell cycle arrest. This evidence indicates that FoxO1 integrates and orchestrates responses to different stress signals to maintain bone cell function and preserve skeletal homeostasis.

Aging

physiology

41709839

A Risky Business--Assessing Breast Cancer Risk

An analysis of BRCA1 and BRCA2 mutations in female relatives of carriers identified among 1008 breast cancer patients has provided revised estimates for the breast cancer risk associated with these mutations. In a Perspective, [Levy-Lahad and Plon][1] discuss these revised estimates reported by the New York Breast Cancer Study ([ King et al ][2].) and what they reveal about the influence of nongenetic factors on breast cancer susceptibility. [1]: http://www.sciencemag.org/cgi/content/full/302/5645/574 [2]: http://www.sciencemag.org/cgi/content/short/302/5645/643

Breast Neoplasms

genetics

17722116

Distribution of colon cancer cells permanently labeled by lectin-mediated endocytosis of a trap label.

A method was elaborated for high-yield 125I-trap labeling of rat colon carcinoma cells using conjugates of dichlorotriazine aminofluorescein and bovine serum albumin substituted with either N-acetylgalactosamine or N-acetylglucosamine as vehicles. Fluorescence microscopy revealed that the ligands accumulated in perinuclear vesicles that were probably lysosomes. Monensin inhibited accumulation by 40%, signifying receptor-mediated endocytosis. Competition experiments revealed that the same receptor(s) mediated endocytosis of the two neoglycoproteins. Accumulation of label was greatly enhanced in the absence of serum, resulting in a labeling efficiency of at least 15 cpm/cell, with no sign of toxic effects. At least 75% of the initially accumulated radioactivity resided in the cells 4 days after labeling. After that the loss of radioactivity was linear with time and stabilized at 1.1%/day for at least 2 weeks. Injection of labeled carcinoma cells i.v. into syngeneic rats revealed a very rapid clearance from the circulation. Isolation of the liver cells 24 h later revealed that a great proportion of the administered cells or their remnants had been engulfed by sinusoidal Kupffer and endothelial cells; the parenchymal cells contained a smaller proportion of label. In conclusion, we have developed a technique of labeling colon carcinoma cells with 125I and fluorescein utilizing specific lectin-like receptors for endocytosis. Since the label is trapped intralysosomally, it will also label Kupffer cells and other members of the reticuloendothelial system after internalization. These features make the procedure well suited for studies on the fate of the colon carcinoma cells after administration in vivo. Since the label is trapped intralysosomally for an extended length of time, parameters such as the formation of metastasis and elimination by phagocytosis can readily be determined.

Adenocarcinoma

pathology

59251107

CDK4/6 inhibitor palbociclib enhances the effect of pyrotinib in HER2-positive breast cancer.

Human epidermal growth factor receptor 2 (HER2) is amplified in about 20% breast cancers. Treat of HER2 positive breast cancers has been greatly promoted in last few years, but the accompany HER2 blockade has hindered the therapeutic effect. Pyrotinib is a pan-HER kinase inhibitor that suppresses signaling through the RAS/RAF/MEK/MAPK and PI3K/AKT pathways. Palbociclib is a CDK4/6 inhibitor that inhibits cell cycle progression and cancer cell proliferation in ER+ breast cancers. We hypothesized that the combination of pan-HER kinase inhibitors and CDK4/6 inhibitors would show synergistic antitumor activity in vivo in vitro. Our data show that a combination of palbociclib and pyrotinib was highly synergistic in inhibiting cancer proliferation and colony formation. The combined treatment also induced significant decreases in pAKT and pHER3 activation, induced G0-G1 cell cycle arrest, and increased rates of apoptosis. In the xenograft model, the combination treatment demonstrated greater antitumor activity than either agent alone, with no apparent increase in toxicity. Our results offer a preclinical rationale clinical investigation of the effectiveness of a combination treatment of palbociclib with pyrotinib for breast cancer treatment.

Breast Neoplasms

drug therapy

15018462

Quantitative predictivity of carcinogenicity of the autoradiographic repair test (primary hepatocyte cultures) for a group of 80 chemicals belonging to different chemical classes.

In this work we have investigated the correlation existing between a short-term genotoxicity test (DNA repair in rat liver cells) and carcinogenicity in rodents. The work is in the framework of a line of thinking that considers as a possibility the utilization of the quantitative component of the information obtained from genotoxicity tests. In a preliminary report for 25 compounds belonging to different chemical classes, a correlation coefficient of 0.36 was found between carcinogenic potency in small rodents and potency in autoradiographic repair. This level of correlation is comparable with similar levels found for many other short-term tests: Ames test, alkaline DNA fragmentation in vivo, DNA adducts in vivo, morphological transformation in vitro and SCE induction in vivo. Obviously, since only 25 compounds were examined, assessment was rather uncertain, and the subdivision of the set into subsets for different chemical classes would have generated groups too small for a meaningful statistical analysis. With a much larger set (80 compounds) we hoped to be able to discriminate different predictivities for different chemical classes. This seems important because the test could be much more suitable for one given class than for another. Previous investigations with different short-term tests have shown that these differences can indeed exist and be very great. In this respect it is potentially very encouraging that the test considered here showed a fair correlation with carcinogenic potency for aromatic amines. Many other tests that we have examined so far have shown little or no predictivity for this important class of chemicals.

Liver

drug effects

205893536

From "hemoabzymes" to "hemozymes": towards new biocatalysts for selective oxidations.

The design of artificial hemoproteins that could catalyze selective oxidations using clean oxidants such as O2 or H2O2 under ecocompatible conditions constitutes a real challenge for a wide range of industrial applications. In vivo, such reactions are performed by heme-thiolate proteins, cytochromes P450, which catalyze the oxidation of substrates by dioxygen in the presence of electrons delivered from NADPH by cytochrome P450 reductase. Several strategies were used to design new artificial hemoproteins that mimic these enzymes. The first one involved the non-covalent association of synthetic hemes with monoclonal antibodies raised against these cofactors. This led to the first generation of artificial hemoproteins or "hemoabzymes" that displayed a peroxidase activity, and in some cases catalyzed the regioselective nitration of phenols by H2O2/NO2 and the stereoselective oxidation of sulfides by H2O2. The second one involved the non-covalent association of easily affordable non-relevant proteins with metalloporphyrin derivatives, using either the "Trojan Horse strategy" or the "host-guest" strategy. This led to a second generation of artificial hemoproteins or "hemozymes", some of which were found able to catalyze the stereoselective oxidation of organic compounds such as sulfides and alkenes by H2O2 and KHSO5.

Proteins

metabolism

19667779

The formation of glutamatergic synapses in cultured central neurons: selective increase in miniature synaptic currents.

The formation of synapses between cultured rat thalamic neurons was studied with electrophysiological and immunocytochemical methods. Thalamic neurons in culture form predominantly glutamatergic synapses. Already after 3 days in vitro glutamatergic miniature EPSCs occurred spontaneously and their frequency was strongly increased after K+ depolarization, while GABAergic mIPSCs were found after K+ depolarization at lower frequency. This demonstrates that both, excitatory glutamatergic and inhibitory GABAergic synapses were functional in close succession to initial neurite outgrowth. Synapses formed independent of spontaneous electrical activity, which was absent during the first week in culture. Spontaneous action potentials appeared during the second week and chronic action potential blockade by addition of tetrodotoxin reduced neuronal survival and the number of glutamatergic synapses per neuron. During in vitro differentiation the number of synapsin I immunoreactive presynaptic terminals and the frequency of spontaneous glutamatergic miniature EPSCs increased closely correlated, while the frequency of GABAergic mIPSCs after K+ depolarization did not increase. Thus, the continous formation of presynaptic terminals, including possible maturation of transmitter release, appeared to underlie the increase in mEPSC frequency. Analysis of miniature EPSC amplitudes at different stages in vitro revealed an increase in amplitudes, suggesting synaptic differentiation after initial establishment of functional transmission in glutamatergic synapses. This process was synapse specific as amplitudes of GABAergic mIPSCs were invariant.

Neurons

physiology

27470834

The effect of eradication therapy on histological changes in the gastric mucosa in patients with non-ulcer dyspepsia and Helicobacter pylori infection. Prospective randomized intervention study.

BACKGROUND/AIMS Eradication therapy results in the control of gastritis. Little is known about its influence on changes in the topographic distribution and regression of specific mucosal alterations in patients with dyspepsia. Our previous study has shown the complex pathological changes in the cardia, corpus and antrum in patients with Helicobacter pylori (H. pylori) infection and NUD. To determine the effect of eradication therapy on the development of histological changes in the lower esophagus, cardia, corpus and antrum in patients with nonulcerous dyspepsia, 3 and 6 months after therapy. METHODOLOGY Two hundred and fifty-one consecutive patients with dyspepsia (the presence of ulcer and stomach malignancy was ruled out) and H. pylori infection were followed up in a prospective study. Every patient underwent endoscopic examination with eight biopsies taken (antrum, corpus, cardia and lower esophagus) before, and 3 and 6 months after eradication therapy (Pantoprazole 40 mg daily, Amoxycilline 1000 mg b.i.d., Clarithromycine 500 mg b.i.d.). The biopsies were stained by (H&E) and Giemsa's staining modified for H. pylori detection. The inflammation, its activity, H. pylori and other mucosal alterations were investigated semi-quantitatively and assessed according to the Sydney system. RESULTS In the cardia, corpus and antrum, significant decrease in chronic inflammation, and H. pylori activity (p<0.001) was found. Atrophy was insignificantly higher in the cardia (p<0.05), whereas in the corpus (p<0.05) and antrum (p<0.001) it was lower. Intestinal metaplasia remained unchanged in the cardia and in the antrum; in the corpus an insignificant decrease was found. The number of patients with foveolar hyperplasia in the cardia was higher, but this increase was not significant, in contrast to the corpus (p<0.01) and antrum (p<0.05). This was especially the case between the first and the second visit. Regression of lymphoid follicles was significant in the cardia (p<0.001) and in the antrum (p<0.01), whereas their quantity in the corpus was unchanged. In the corpus and antrum, a significant increase of chemical gastropathy between the second and third visit (p<0.001) was found. The same applied for hemorrhages found in the esophagus papillae (p<0.001). CONCLUSIONS Eradication therapy was closely associated with a significant decrease of inflammation activity and H. pylori infection. Chronic inflammation, mucosal atrophy and intestinal metaplasia persisted, even though their intensity was decreased, and signs of chemical gastropathy with hemorrhages in the esophageal papillae were found.

Anti-Bacterial Agents

therapeutic use

26245833

Intestinal immune response of volunteers ingesting a strain of enteroadherent (HEp-2 cell-adherent) Escherichia coli

Enteroadherent Escherichia coli (EAEC) strains identified by adherence to HEp-2 tissue culture cells have been incriminated epidemiologically as important etiologic agents of diarrheal disease in both adult travelers and children in developing countries. One strain, JM 221, with no recognized E. coli virulence characteristics other than adherence to HEp-2 cells, caused diarrhea in 5 of 16 volunteers ingesting it. We studied the secretory immunoglobulin A (sIgA) responses to EAEC JM 221 of five volunteers with diarrhea and five volunteers who remained healthy after challenge. sIgA was extracted from stools obtained prechallenge and 7 days postchallenge. Total sIgA was standardized for all specimens. Specific sIgA titers were determined by dot blotting with the following JM 221 antigens: water-extractable surface antigens, whole cells, lipopolysaccharides, and outer membrane proteins. All five subjects who became ill had fourfold or greater rises in titers against each of the four antigens. The five subjects who remained healthy following challenge did not exhibit significant rises in titers to any JM 221 antigens, but their mean titers were significantly higher than the mean prechallenge titers of the volunteers with diarrhea, suggesting that high intestinal sIgA titers may be protective. The significant increases in intestinal antibody against JM 221 in the subjects who became ill is further evidence of the enteropathogenicity of EAEC strains.

Escherichia coli

immunology

222160891

Synthetic Multienzyme Complexes Assembled on Virus-like Particles for Cascade Biosynthesis In Cellulo.

Multienzyme complexes, or metabolons, are natural assemblies or clusters of sequential enzymes in biosynthesis. Spatial proximity of the enzyme active sites results in a substrate channeling effect, streamlines the cascade reaction, and increases the overall efficiency of the metabolic pathway. Engineers have constructed synthetic multienzyme complexes to acquire better control of the metabolic flux and a higher titer of the target product. As most of these complexes are assembled through orthogonal interactions or bioconjugation reactions, the number of enzymes to be assembled is limited by the number of orthogonal interaction or reaction pairs. Here, we utilized the Tobacco mosaic virus (TMV) virus-like particle (VLP) as protein scaffold and orthogonal reactive protein pairs (SpyCatcher/SpyTag and SnoopCatcher/SnoopTag) as linker modules to assemble three terpene biosynthetic enzymes in Escherichia coli. The enzyme assembly switched on the production of amorpha-4,11-diene, whereas the product was undetectable in all the controls without assembly. This work demonstrates a facile strategy for constructing scaffolded catalytic nanomachineries to biosynthesize valuable metabolites in bacterial cells, and a unique assembly induced the switch-on mechanism in biosynthesis for the first time.

Escherichia coli

metabolism

8208445

Localisation of monoclonal antibodies reacting with different epitopes on carcinoembryonic antigen (CEA)--implications for targeted therapy.

Antibody targeting has potential for selective delivery of cancer therapy. However, there is a wide variation in the degree of antibody localisation in individual patients with colorectal adenocarcinoma. Colorectal adenocarcinomas are composed of glandular structures separated from fibrovascular stroma by a basal lamina which may represent a significant barrier to extravasated antibody. Basement membrane-associated CEA epitopes may be more accessible to antibodies than those which are cytoplasmic or lumenal. We have investigated by immunohistochemistry and in vivo localisation, the extent to which distribution of antigen epitopes influences targeting. Two monoclonal antibodies (A5B7 and EA77) recognising non-overlapping CEA epitopes were reacted immunohistochemically with samples of 39 tumours. Intensity and site of reaction were assessed for basement membrane, cytoplasmic or lumenal surface association. 125I-labelled antibodies were injected into nude mice bearing LS174T tumour. Per cent injected activity per gram was measured in tumour and normal tissues, 24, 72 and 168 h later. Tissues reacted immunohistochemically for CEA were autoradiographed to assess the relationship of injected antibody to target antigen. Immunohistochemistry showed that A5B7 antibody favours basement membrane aspects of malignant glands; in contrast, EA77 concentrated generally on lumenal surfaces. In vivo localisation showed that per cent inj.act g-1 in tumour for A5B7 reached 36.5% at 24 h. EA77 localised to a lesser extent (9.1% at 24 h), despite a longer circulatory half-life. Autoradiography combined with immunohistochemistry showed A5B7 reacting with antigen close to vasculature after 24 h, slowly penetrating deeper parts of the tumour by 72 h. In contrast, EA77 was confined mainly to fibrovascular stroma, showing little labelling of antigen-positive tumour cells. Localisation differences between A5B7 and EA77 may partly be due to accessibility of epitopes on tumour cells.

Adenocarcinoma

immunology

35056784

Early Occurrence of Angiosarcoma in a Woman With a BRCA2 Gene Variation of Unknown Significance Treated With Breast-Conserving Therapy for Bilateral Ductal Carcinoma: A Case Report.

Radiation-associated angiosarcoma (RAAS) develops in the setting of lymphedema or previous radiation; patients typically present with cutaneous lesions rather than parenchymal lesions. RAAS can present as early as 6 months after completion of radiotherapy, and skin punch biopsy of suspicious cutaneous lesions should be performed. BRCAmutations may play a role in in the development of breast RAAS. However, this still requires further study.

Breast Neoplasms

pathology

3184869

Quantitative three-dimensional analysis and diffusion modeling of oligonucleotide concentrations after direct intraparenchymal brain infusion

We compared quantitative experimental results on the diffusion of /sup 35/S-labeled phosphorothioate oligonucleotide (PS-ODN) after intraparenchymal infusion in rat brain, with the distributions predicted by Fick's second law of diffusion. Fischer 344 rats underwent identical intracerebral infusions of /sup 35/S-PS-ODN. After 0, 5, 11, 23, and 47 h, groups of animals were sacrificed and sequential brain cryosections subjected to autoradiography. The resulting experimental data were compared to the predicted distributions, for estimation of the apparent free diffusion coefficient, D*. Volumes of distribution and total content of /sup 35/S-PS-ODN in the parenchyma were also computed, to monitor loss of total material. The values for D* were within the expected range for the 21-mer PS-ODN used, but a progressive decrease in D* over time was noted. The model requires D* to remain constant and, thus, does not adequately explain the spread of /sup 35/S-PS-ODN following infusion. The progressive slowing of spread over time suggests that at later time points, /sup 35/S-PS-ODN may be fixed by tissue binding or cellular uptake in the brain. Loss of material via vascular and CSF clearance may also contribute to the lack of fit. Our results highlight issues to be addressed in the modeling and experimental design of the intraparenchymal infusion process.

Brain

metabolism

18306312

Modulation of protein-protein interactions by stabilizing/mimicking protein secondary structure elements.

In view of the crucial role of protein-protein intercommunication both in biological and pathological processes, the search of modulators of protein-protein interactions (PPIs) is currently a challenging issue. The development of rational strategies to imitate key secondary structure elements of protein interfaces is complementary to other approaches based on the screening of synthetic or virtual libraries. In this sense, the present review provides representative examples of compounds that are able to disturb PPIs of therapeutic relevance, through the stabilization or the imitation of peptide hot-spots detected in contact areas of the interacting proteins. The review is divided into three sections, covering mimetics of the three main secondary structural elements found in proteins, in general, and in protein-protein interfaces, in particular (alpha-helices, beta-sheets, and reverse turns). Once the secondary element has been identified, the first approach typically involves the translation of the primary peptide structure into different cyclic analogues. This is normally followed by gradual decrease of the peptide nature through combination of peptide and non-peptide fragments in the same molecule. The final step usually consists in the development of pertinent organic scaffolds for appending key functional groups in the right spatial disposition, as a means towards totally non-peptide small molecule PPI modulators.

Proteins

physiology

8148395

The fornix and limbic system.

The limbic system is predominantly involved in memory and emotional output. Its 2 principle components are the hippocampus (involved in memory as part of the Papez circuit) and the amygdala (involved in emotional responses, memories and drives). The principle clinical manifestations of limbic disease are epilepsy, confusional states, and cognitive impairment. The connections of the limbic system are widespread and are now becoming visible on diffusion tensor imaging. Many different diseases may affect the limbic system. An appreciation of its functional anatomy along with its white matter tract connections improves assessment of infiltrative disease in particular. Small lesions in the Papez circuit may have devastating neuropsychological consequences. An active search strategy based on the knowledge presented in this paper will increase the likelihood of making an accurate diagnosis for patients affected by these conditions.

Mental Disorders

pathology

40941242

Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index

The melanocortin-4 receptor gene ( MC4R ) is involved in central energy homeostasis and body weight regulation. Both endogenous anorexigenic and orexigenic ligands bind to the receptor.1 Under normal conditions, the anorexigenic tone prevails as revealed by the fact that Mc4r knock-out mice2 develop elevated body weight. Mc4r−/− mice show higher food intake but a similar metabolic rate and similar decreased physical activity compared to wild type (WT) mice of the same strain.2–4 In comparison to a standard low fat diet, this deviant regulation of energy homeostasis is even more pronounced upon intake of a moderately fat diet,5 which leads to an even higher body mass. In all studies, the effect on body weight is smaller in heterozygous than in homozygous knockout mice, but the exact degree of dominance is not clear. In heterozygous Mc4r+/− animals, body mass is increased on average by about 7–45% and in homozygous Mc4r−/− by 50–100% compared to WT2–5 with substantial overlap between groups. The mutations might have a sex dependent effect, but the results are contradictory. In one study, the effect in males was only about half of that in females.2 However, two studies did not detect a sex by genotype interaction in this Mc4r−/− strain.4,5 One study in a different knockout line of the same inbred strain found a sex by genotype interaction in the opposite direction, with only a marginal effect in heterozygous females whereas heterozygous males had a body weight intermediate between WT and homozygous knockouts.3 The first mutations in the human MC4R gene were reported in extremely obese probands.6–8 Since then, several other studies investigated the association of different MC4R mutations with obesity. According to a recent overview,9 at least 34 putatively functionally relevant …

Obesity

genetics

59225456

Supplemental ultrasound screening in patients with a history of lobular neoplasia

To investigate the role of ultrasound (US) screening as an adjunct to annual mammography (M) in breast cancer detection in women with a history of lobular neoplasia (LN) diagnosed following core needle or excisional biopsy. A retrospective review of our database was performed between 11/2006 and 11/2011 to identify patients diagnosed with LN, and underwent annual screening. Patients with a lifetime risk >20% per risk modeling were excluded. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and cancer detection rate (CDR) of each screening test were identified. Cancer type and detection modality were recorded. A total of 100 patients who had M and/or US screening were included. Mean patient age was 54.7 years (range 33‐83). All 100 patients underwent a mean of 3.9 rounds of screening M and 93 (93%) received US screening (mean 3.3 rounds). Of 93 patients who received both M and US screening, 12 (13%) were diagnosed with breast cancer. Mammographic CDR was 4%. Incremental US CDR was 6.5%. The sensitivity, specificity, and NPV for M screening alone was 33% (10%, 65%), 77% (67%, 85%), and 89% (80%, 95%), respectively. US and mammography screening had a combined sensitivity: 83% (52%, 98%), Specificity: 72% (62%, 81%), NPV: 97% (89%, 100%). Supplemental US screening resulted in a significant increase in sensitivity, yielding 6.5% incremental CDR in this high‐risk patient subgroup that does not fulfill ACS high‐risk MRI screening criteria.

Breast Neoplasms

diagnostic imaging

12330372

Racial Differences in Stage and Survival in Head and Neck Squamous Cell Carcinoma

Objectives: The goal of this study was to characterize differences in survival between black patients and white patients with squamous cell carcinoma of the head and neck (HNSCCA).

Carcinoma, Squamous Cell

ethnology

4650503

Relationship between Bone Mineral Density and Body Composition Estimated by Dual-Energy X-ray Absorptiometry: Comparison between Groups Aged 20-39 and 40-59 Years.

Bone mineral density (BMD) is affected by lean body mass and body weight to various degrees in the course of aging. The attempt of this study is to determine the optimal time to begin prevention of osteoporosis. In this study, female hospital employees aged 20-59 years were divided into 2 age groups, 20-39 years and 40-59 years based on age at peak BMD, and the relations of total BMD, subtotal BMD and lumbar spine BMD to lean body mass and body weight were examined in both groups. Subtotal BMD was calculated by subtracting head BMD from total BMD along with whole body measurement. While persistent positive correlations were found among all factors in the 20-39-year-old group, subtotal BMD and lumbar spine BMD were positively correlated to lean body mass in the 40-59-year-old group. Thus, lean body mass and body weight appeared to exert a profound influence on subtotal BMD in those aged 20-39 years, but lean body mass in those aged 40-59 years. Lean body mass appears to provide the best prediction of subsequent development of osteoporosis.

Aging

physiology

53303260

Effects of Cardiovascular Risk Factors on Cardiac STAT3

Nuclear, mitochondrial and cytoplasmic signal transducer and activator of transcription 3 (STAT3) regulates many cellular processes, e.g., the transcription or opening of mitochondrial permeability transition pore, and its activity depends on the phosphorylation of Tyr705 and/or Ser727 sites. In the heterogeneous network of cardiac cells, STAT3 promotes cardiac muscle differentiation, vascular element formation and extracellular matrix homeostasis. Overwhelming evidence suggests that STAT3 is beneficial for the heart, plays a role in the prevention of age-related and postpartum heart failure, protects the heart against cardiotoxic doxorubicin or ischaemia/reperfusion injury, and is involved in many cardioprotective strategies (e.g., ischaemic preconditioning, perconditioning, postconditioning, remote or pharmacological conditioning). Ischaemic heart disease is still the leading cause of death worldwide, and many cardiovascular risk factors contribute to the development of the disease. This review focuses on the effects of various cardiovascular risk factors (diabetes, aging, obesity, smoking, alcohol, depression, gender, comedications) on cardiac STAT3 under non-ischaemic baseline conditions, and in settings of ischaemia/reperfusion injury with or without cardioprotective strategies.

Cardiovascular Diseases

metabolism

10525062

Daily oral grepafloxacin vs. twice daily oral doxycycline in the treatment of Chlamydia trachomatis endocervical infection.

OBJECTIVE: To compare the efficacy and safety of a 7-day course of treatment with oral grepafloxacin, 400 mg once daily, and oral doxycycline, 100 mg twice daily, in patients with chlamydial cervicitis. METHODS: Women aged 18 years or older attending 17 sexually transmitted disease clinics in the United States who had clinical signs of mucopurulent cervicitis or who had a recent positive culture or nonculture test for Chlamydia trachomatis or who had contact with a male partner with a positive culture for C. trachomatis were enrolled into this randomized, double-blind, active-controlled clinical study. The diagnosis of chlamydial cervicitis was based on culture for C. trachomatis. Patients were randomized to receive a 7-day course of treatment with either oral grepafloxacin, 400 mg once daily, or oral doxycycline, 100 mg twice daily. Response to therapy was assessed 3-8 days and 21-28 days after completion of treatment. The primary measure of efficacy was eradication of C. trachomatis at the 21-28 day follow-up visit. Clinical success, defined as improvement or complete resolution of the signs and symptoms of cervicitis, was a secondary measure of efficacy. RESULTS: Of the 451 female patients enrolled, 228 received grepafloxacin and 223 received doxycycline. In all, 154/451 (35%) patients were evaluable at the 21-28 day follow-up (81 who received grepafloxacin and 73 who received doxycycline). Microbiologic and clinical success rates demonstrated the equivalence of the two treatments. The C. trachomatis eradication rates were 96.3% (78/81) and 98.6% (72/73) for patients receiving grepafloxacin or doxycycline, respectively. The two study drugs were also equivalent in resolving clinical signs and symptoms, with clinical success rates of 88.9% (64/72) and 89.5% (51/57) for patients treated with grepafloxacin and doxycycline, respectively. Both drugs were well tolerated, with 47% of patients receiving grepafloxacin and 46% of patients receiving doxycycline experiencing drug-related adverse events, none of which was serious. CONCLUSIONS: Seven days of treatment with oral grepafloxacin, 400 mg once daily, was as effective as 7 days of treatment with oral doxycycline, 100 mg twice daily, in patients with cervicitis caused by C. trachomatis. Both agents were well tolerated and had comparable safety profiles. Grepafloxacin's once-daily dosing regimen may offer advantages in terms of patient compliance.

Anti-Bacterial Agents

administration & dosage

21602007

Cerebral MRI and spectroscopy in Sjögren-Larsson syndrome: Case report

We report MRI and MRS of the brain in a patient with Sjögren-Larsson syndrome (SLS) in whom fatty alcohol oxidoreductase (FAO) deficiency has been verified. MRI showed periventricular lesions, high intensity on T2-weighted and low intensity on T1-weighted images at trigones of the lateral ventricles.1H-MRS of these lesions revealed high lipid and low N-acetyl aspartate peaks. We presume such lipids in periventricular lesions with high T2 signal may be pathognomonic of SLS.

Brain

pathology

89202135

The effect of 5-hydroxytryptamine and histamine on glycolysis in the mouse brain.

Following the intraventricular injection of 5-hydroxytryptamine into the lateral ventricles of conscious mice, the concentration of brain lactate rose immediately but then decreased significantly compared with the saline injected controls. The concentration of brain glucose increased 20 min after the injection of 5-hydroxytryptamine. These effects of 5-hydroxytryptamine on lactate and glucose were qualitatively similar to those found following the administration of methysergide. After the parenteral administration of 5-hydroxytryptophan, the lactate levels showed a bephasic change but brain glucose was significantly decreased for up to 90 min following the injection. p-Chlorophenylalanine potentiated the effect of 5-hydroxytryptamine by further increasing glucose and decreasing lactate levels. After histamine had been injected into the ventricles, the concentrations of bound glycogen and lactate were decreased whereas free glycogen and glucose were raised. It is suggested that 5-hydroxytryptamine, and possibly histamine, are involved with control of glycolysis in the mouse brain.

Brain

drug effects

21206311

Turning the Tide Against Cancer Through Sustained Medical Innovation: The Pathway to Progress

An ever-expanding understanding of the molecular basis of the more than 200 unique diseases collectively called cancer, combined with efforts to apply these insights to clinical care, is forming the foundation of an era of personalized medicine that promises to improve cancer treatment. At the same time, these extraordinary opportunities are occurring in an environment of intense pressure to contain rising healthcare costs. This environment presents a challenge to oncology research and clinical care, because both are becoming progressively more complex and expensive, and because the current tools to measure the cost and value of advances in care (e.g., comparative effectiveness research, cost-effectiveness analysis, and health technology assessments) are not optimized for an ecosystem moving toward personalized, patient-centered care. Reconciling this tension will be essential to maintaining progress in a cost-constrained environment, especially because emerging innovations in science (e.g., increasing identification of molecular biomarkers) and in clinical process (implementation of a learning healthcare system) hold potential to dramatically improve patient care, and may ultimately help address the burden of rising costs. For example, the rapid pace of innovation taking place within oncology calls for increased capability to integrate clinical research and care to enable continuous learning, so that lessons learned from each patient treated can inform clinical decision making for the next patient. Recognizing the need to define the policies required for sustained innovation in cancer research and care in an era of cost containment, the stakeholder community must engage in an ongoing dialogue and identify areas for collaboration. This article reflects and seeks to amplify the ongoing robust discussion and diverse perspectives brought to this issue by multiple stakeholders within the cancer community, and to consider how to frame the research and regulatory policies necessary to sustain progress against cancer in an environment of constrained resources. Clin Cancer Res; 20(5); 1081–6. ©2014 AACR.

Neoplasms

therapy

53719507

The feasibility, acceptability and outcomes of exergaming among individuals with cancer: a systematic review

BackgroundIndividuals with cancer have reduced quality of life, functionality, range of motion, strength, and an increase in pain and fatigue. Exergaming appears to be an effective rehabilitation tool for Parkinson’s disease, multiple sclerosis and post-stroke patients to improve functionality, balance and quality of life; however, the usefulness of exergaming in individuals with cancer is unknown. The aim of this systematic review is to describe exergaming interventions delivered to adults with a current or previous cancer diagnosis and to report the feasibility, acceptability and outcomes of such interventions.MethodsStudies reporting on exergaming interventions delivered to individuals with a current or previous cancer diagnosis were included. 12 electronic databases were searched. Eight articles (seven interventions) were identified. Data were extracted and assessed for quality by two reviewers.ResultsThree interventions were delivered at hospital, two at home, one at a clinical laboratory, and one did not report. Two interventions were delivered by a physiotherapist, two by an occupational therapist, and one by a nurse, research staff and an exercise physiologist. The Nintendo Wii was used in four of seven studies, whilst the remaining three used the IREX system, BrightArm Duo Rehabilitation System or a custom made exergame. Studies showed that most participants enjoyed the exergaming intervention, and would recommend their use, with some preferring exergaming over standard care interventions. Adherence rates and enjoyment appear greater during exergaming than standard care. Exergaming interventions appear to support improvements balance, function, physical activity levels, strength, fatigue, emotions, cognition and pain.ConclusionExergaming interventions delivered to individuals with cancer show great heterogeneity; differing in duration, frequency and gaming platform. The disease stage and severity of those included, and the outcome measures assessed also vary widely making it difficult to conclude its effectiveness at this time. However, adherence rates and enjoyment appear greater during exergaming compared to standard care, supporting the feasibility and acceptability of this type of intervention delivery for adults with cancer.

Neoplasms

rehabilitation

6196867

Pulmonary PKG-1 is upregulated following chronic hypoxia.

Recent studies from our laboratory indicate that pulmonary vasodilatory responses to exogenous nitric oxide (NO) are attenuated following chronic hypoxia (CH) and that this NO-dependent vasodilation is mediated by cGMP. Similarly, we have demonstrated that CH attenuates vasodilatory responses to the cGMP analog 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP). We hypothesized that attenuated pulmonary vasodilation to 8-BrcGMP following CH is mediated by decreased protein kinase G-1 (PKG-1) expression/activity. Therefore, we examined vasodilatory responses to 8-BrcGMP (1 microM) in isolated, saline-perfused lungs from control and CH (4 wk at barometric pressure of 380 mmHg) rats in the presence of the competitive PKG inhibitor Rp-beta-phenyl-1, N2-etheno-8-bromoguanosine 3',5'-cyclic monophosphorothionate (30 microM) or the highly specific PKG inhibitor KT-5823 (10 microM). PKG-1 expression and activity were determined in whole lung homogenates from each group, and vascular PKG-1 levels were assessed by quantitative immunohistochemistry. PKG inhibition with either Rp-8-Br-PET-cGMPS or KT-5823 diminished vasodilatory responses to 8-BrcGMP in lungs from both control and CH rats, thus indicating a role for PKG in mediating reactivity to 8-BrcGMP in each group. However, in contrast to our hypothesis, PKG-1 levels were approximately twofold greater in lungs from CH rats vs. controls, and furthermore, this upregulation was localized to the vasculature. This correlates with an increase in PKG activity following CH. We conclude that PKG-1 is involved in 8-BrcGMP-mediated vasodilation; however, attenuated pulmonary vasodilation following CH is not associated with decreased expression/activity of PKG-1.

Lung

enzymology

34750757

Clear cell acanthoma: clinicopathologic analysis of 37 new cases.

The clinical and histologic features of 37 new cases of clear cell acanthoma were analyzed. All lesions were solitary; most were asymptomatic, erythematous nodules less than 1 cm. in diameter. The median age of the patients was 64 years, the median duration of the lesions was 3 years, and the incidences in both sexes were equal. Thirty-five of the tumors occurred on the lower limbs. Many were clinically interpreted as basal cell carcinoma, histiocytoma, or granuloma pyogenicum. Histologic examination disclosed acanthotic rete ridges with large, pale, glycogen-rich malpighian cells covered by serous crust and parakeratotic scale. At each margin there was a sharp transition to dark cell acanthosis in two or three rete ridges which were covered by thick horn and a hyperplastic granular layer. Lateral to this was a second transition to normal epidermis. Rich vascularity and a perivascular lymphocytic infiltrate were present in the cutis.

Carcinoma, Squamous Cell

pathology

37067276

An angiotensin II receptor blocker increases sexual behavior in type 2 diabetic mice

The present study was conducted to examine the effects of olmersartan, angiotensin (ANG) II type 1 (AT(1)) receptor antagonist, on the sexual function in type 2 diabetes model mice. Twenty-week-old KK/Ta mice were used as a model of type 2 diabetes. Age-matched ICR and BALB/C mice were used as non-diabetic controls. The animals were fed powder chow either with or without olmesartan (7.5 microg/g in chow) for 4 weeks. The levels of sexual behavior, activity, and anxiety were then examined between the groups treated with and without olmesartan. The KK/Ta mice treated with olmesartan exhibited a significant increase in the number of mounts and intromission and a decrease in the latency to the first mount in comparison to the KK/Ta mice treated without olmesartan. These effects of olmesartan were not observed in the non-diabetic BALB/C and ICR mice. In addition, the olmesartan treatment did not affect the activity and anxiety regardless of the mouse strain. These findings suggest that the interaction between ANG II and AT(1) receptor may be involved in the pathogenesis of the sexual dysfunction associated with type 2 diabetes and a blockade of ANG II may therefore be a potentially useful treatment for male sexual dysfunction in type 2 diabetes.

Diabetes Mellitus, Type 2

complications

25503821

Successful treatment of c-kit-positive metastatic Adenoid Cystic Carcinoma (ACC) with a combination of curcumin plus imatinib: A case report.

Adenoid cystic carcinoma (ACC) is an aggressive malignant neoplasm of the secretory glands. Conventional chemotherapy has poor effectiveness against metastatic ACC. Thus, a novel effective therapy is needed against metastatic ACC. A majority of ACCs (up to 94%) express c-kit. Imatinib is monoclonal antibody with specific activity against c-kit but has not been found to be effective in treating patients with ACC in which c-kit is overexpressed and activated. The NF-κB and mTOR pathways have been shown that ubiquitously and concurrently activated, indicating that the inhibition of these pathways may represent a novel treatment approach for patients with ACC. Curcumin has been shown to inhibit NF-κB and NF-κB-related pathways. 43-year-old patient was diagnosed ACC from submandibular salivary gland. After complete resection of tumor adjuvant radiotherapy was initiated. Seven years later multiple lung metastases were detected and ACC was confirmed by re-biopsy. First-line chemotherapy failed. NF-κB and c-kit were overexpressed in the metastatic specimens. Therefore, we treated the patient with metastatic chemoresistant ACC with imatinib 400mg/day and intravenous curcumin 225mg/m(2) twice a week plus oral bioavailable curcumin Arantal(®) 2×84mg/day. At 24 months, we observed near complete anatomic and complete metabolic response. To our knowledge, this is the first report of a patient with a c-kit-positive ACC that is successfully treated with the combination of imatinib and curcumin in an integrative approach.

Antineoplastic Agents

therapeutic use

24865492

[Total proteins levels and embryonic development of eggs of sea urchins (Lytechinus variegatus) treated with YbCl3].

Total proteins levels and the embryonic development of sea urchin (Lytechinus variegatus) eggs treated with 25 micrograms/ml of YbCl3 in sea water for one hour were studied. After the treatment, eggs were let to develop for 24 hours when the total proteins levels were determined and morphological changes as well as the synchronism of the embryonic development have been checked.

Proteins

analysis

213181495

Use of home visits in pediatric severe asthma: randomized controlled trial.

OBJECTIVE To evaluate the effectiveness of home visits in a group of children and adolescents with severe asthma by using the inhalation technique score and adherence rates to drug treatment. METHOD A 12-month randomized controlled trial involving patients aged between three and 17 years under regular follow-up treatment at a pediatric pulmonology outpatient clinic of a university hospital in southeastern Brazil. A group of patients received only outpatient consultations and the other group received home visits from nurses in addition to outpatient consultations. The differences between groups were analyzed through the outcomes of inhalation technique scores and treatment adherence rate. RESULTS Participation of 29 patients. In the intervention group, there was a statistically significant increase in inhalation technique scores (p<0.05) and elimination of critical errors between the first and the second evaluation, and results were maintained in the third evaluation. In the control group, there were no significant changes in inhalation technique scores. Rates of adherence to drug treatment in both groups did not rise. CONCLUSION Home visits were effective for improving inhalation technique scores in patients with severe asthma. Brazilian Registry of Clinical Trials: RBR-8GZWZP.

Asthma

drug therapy

46490519

The latex particle adherence assay: inhibitory effects of protein preparations.

The latex particle adherence to peripheral chicken lymphocytes in the presence of different concentrations of various protein preparations was examined. Non-specific inhibition of adherence was observed at and above concentrations of 500 microgram/ml, whereas protein concentrations at and below 250 microgram/ml gave no significant adherence inhibition in control chicken lymphocytes. The protein concentration of 250 microgram/ml of antigens prepared from MDV-infected chicken skin and HPRS-1 cells specifically inhibited the LPA to lymphocytes of MDV-infected chickens.

Proteins

immunology

22892206

Changes in levels of serum insulin, C-Peptide and glucose after electroacupuncture and diet therapy in obese women.

Our purpose was to investigate the effects of electroacupuncture (EA) therapy on body weight and on levels of serum insulin, c-peptide and glucose in obese women. 52 healthy women were included in this study and were allocated into three groups: 1) Placebo EA group (n = 15; mean age = 41.8 +/- 4.6 and mean body mass index {BMI} = 33.2 +/- 3.5); 2) EA group (n = 20; mean age = 42.1 +/- 4.4 and BMI = 35.9 +/- 3.6) and 3) Diet restriction group (n = 20; mean age = 42.9 +/- 4.3 and BMI = 34.7 +/- 2.7). EA was applied to the ear points Hunger and Shen Men on alternating days and to the body points LI 4, LI 11, St 36 and St 44 once a day for 30 minutes over 20 days. Diet restriction that entailed a 1450 kilocalorie (kcal) diet program was applied to the three groups for 20 days. An increase in weight loss was observed when weight loss in the EA group (p < 0.000) was compared to that in the diet restricted and placebo EA groups using the Tukey HSD test. There were increases in the serum insulin (p < 0.001) and c-peptide levels (p < 0.000) in the women treated with EA compared to those in the women treated with the placebo EA and diet restriction groups. A decrease was observed in the glucose levels (p < 0.01) in both the EA and diet restriction groups compared to those in the placebo EA group. Our results suggest that EA therapy is an effective method in treating obesity. EA therapy also helps serum glucose levels to decrease through the increase of serum insulin and c-peptide levels.

Obesity

blood

72952026

Changes in Dogs’ Lungs After Long-Term Exposure to Ozone

Dogs were exposed to 1 to 3 ppm of ozone (O3) 8 to 24 hours daily for 18 months. Macrophages appeared and increased with “dosage.” Fibrous elements were deposited rarely at the lowest dosage but increased with the concentration of O3. Additional features were thickening of the terminal and respiratory bronchiolar walls at the higher concentrations and their infiltration by lymphocytes, plasma cells, and “fibroblasts” that formed peribronchiolar collars. Connective tissue obstructed alveolar openings into bronchioles and ducts and extended into alveolar walls. Thick bronchiolar walls reduced the caliber of small airways. Bronchiolar epithelial changes included an increase in the proportion of mucus-forming cells and squamous metaplasia of columnar and cuboidal cells with occasional islands of hyperplasia. Metabolic effects were reflected in ultrastructural alteration of preexisting, intracytoplasmic bodies. Together with nitrogen dioxide, O3 may contribute to pulmonary disease in a susceptible population.

Lung

drug effects

23863321

MR imaging of pulmonary parenchyma with a half-Fourier single-shot turbo spin-echo (HASTE) sequence.

OBJECTIVE To evaluate the utility of a half-Fourier single-shot turbo spin-echo sequence (HASTE) at depicting lung parenchyma and lung pathology. METHODS AND PATIENTS A HASTE sequence was applied to five normal volunteers and 20 patients with various pulmonary disorders to depict the lung parenchyma. Images were acquired with ECG-triggering and breath-holding. In three volunteers, signal intensity measurements from lung parenchyma were performed using four sequences: (a) HASTE; (b) conventional spin echo; (c) fast spin echo; and (d) gradient echo. T2 maps were produced using the HASTE acquisition. RESULTS Minimal respiratory or cardiac motion artifacts were observed. The signal-to-noise ratios from lung parenchyma were 27.8 +/- 5.4, 22.0 +/- 3.0, 15.3 +/- 0.9, and 6.0 +/- 1.9 for HASTE, spin-echo, fast spin-echo, and gradient echo sequences, respectively. The scan time for HASTE was 302 ms for each slice. The T2 values in the right lung and the left lung were 61.2 +/- 4.1 and 79.1 +/- 8.9 ms in systole and 92.6 +/- 5.8 and 97.5 +/- 12.2 ms in diastole, respectively (P < 0.05 diastole versus systole). The HASTE sequence demonstrated clearly various pulmonary disorders, including lung cancer, hilar lymphadenopathy, metastatic pulmonary nodules as small as 3 mm, pulmonary hemorrhage, pulmonary edema and bronchial wall thickening in bronchiectasis. CONCLUSION Our preliminary results indicate that the HASTE sequence provides a practical means for breath-hold MR imaging of lung parenchyma.

Lung

anatomy & histology

35642504

Irbesartan/Amlodipine: A Review of its Use in Adult Patients with Essential Hypertension Not Adequately Controlled with Monotherapy

Combination therapy is often required in patients with hypertension, and fixed-dose single-pill combinations have been shown to provide an easier regimen for patients, improving adherence. Irbesartan/amlodipine (Aprovasc®) is an angiotensin-receptor blocker/calcium-channel blocker fixed-dose single-pill combination, whose constituent drugs exert additive effects when coadministered. In two randomized, open-label, multicentre, phase III trials, fixed-dose combination therapy with irbesartan/amlodipine was more effective than continuation of irbesartan or amlodipine monotherapy in patients with hypertension not adequately controlled with initial irbesartan or amlodipine monotherapy; there was a significantly greater decrease from baseline in mean seated home systolic blood pressure (primary endpoint) with the fixed-dose combination. The fixed-dose combination was also associated with a greater decrease in mean seated home diastolic blood pressure and mean seated office systolic and diastolic blood pressure than monotherapy. The fixed-dose combination of irbesartan/amlodipine was well tolerated in these patients; most treatment-emergent adverse events were of mild or moderate severity. The most frequent adverse event was peripheral oedema, generally associated with amlodipine treatment.

Hypertension

drug therapy

36221

The effect of a concentrate of nocardin on the growth of streptomycin sensitive and resistant strains ofMycobacteria Tuberculosis

In 1947 a new tuberculostatic antibiotic, Nocardin, was reported from the Aetinomycete, Nocardia coeliaca (Gray and Thornton) EMMONS. This was found to be active against human tubercle bacilli in vitro; to inhibit tubercle development on the chorio-allantoic membrane of the chick and to partially inhibit the loss of weight in tuberculous guinea pigs (1,2). A crude product extracted from the mycetium was later found to inhibit the development of tubercles in the lungs of tuberculous mice (3). These early findings on the tuberculostatic activity of Nocardin were later verified and the bacteriostatic action in vitro extended by LEVADITI (4) and LEVADITI and HENRY-EVENO (5). The present report is an account of the acti¢Jty in vitro of a more highly purified form of Nocardin. While as yet not in crystalline form, nevertheless, this fraction is water soluble and stable in solution over a two year period. Its activity in vitro against four human strains of tubercle bacilli and their streptomycin resistant biotypes is reported herewith.

Anti-Bacterial Agents

pharmacology

28391688

Primary versus castration-resistant prostate cancer: modeling through novel murine prostate cancer cell lines

Cell lines representing the progression of prostate cancer (PC) from an androgen-dependent to an androgen-independent state are scarce. In this study, we used previously characterized prostate luminal epithelial cell line (Plum), under androgen influence, to establish cellular models of PC progression. Cells derived from orthotopic tumors have been isolated to develop an androgen-dependent (PLum-AD) versus an androgen-independent (PLum-AI) model. Upon immunofluorescent, qRT-PCR and Western blot analyses, PLum-AD cells mostly expressed prostate epithelial markers while PLum-AI cells expressed mesenchymal cell markers. Interestingly, both cell lines maintained a population of stem/progenitor cells. Furthermore, our data suggest that both cell lines are tumorigenic; PLum-AD resulted in an adenocarcinoma whereas PLum-AI resulted in a sarcomatoid carcinoma when transplanted subcutaneously in NOD-SCID mice. Finally, gene expression profiles showed enrichment in functions involved in cell migration, apoptosis, as well as neoplasm invasiveness and metastasis in PLum-AI cells. In conclusion, these data suggest that the newly isolated cell lines represent a new in vitro model of androgen-dependent and –independent PC.

Prostatic Neoplasms

pathology

24644802

Negative autoregulation of cysB in Salmonella typhimurium: in vitro interactions of CysB protein with the cysB promoter

CysB protein positively regulates genes of the Salmonella typhimurium cysteine regulon and negatively autoregulates cysB. The cysB promoter was characterized by primer extension of cellular RNA, which gave products identifying a major in vivo transcription start site located 95 bp upstream of the cysB start codon and two minor sites located 9 and 10 bp downstream of the major site. Gel shift binding studies and DNase I footprinting experiments showed that CysB protein binds to the cysB promoter from position -10 to +36 relative to the major transcription start site. We have designated this binding site CBS-B. CysB protein inhibited transcription initiation at the cysB promoter in an in vitro runoff assay, indicating that cysB is negatively autoregulated by the binding of CysB protein to the cysB promoter, where it acts as a repressor. N-Acetyl-L-serine, an inducer of the cysteine regulon, inhibited the binding of CysB protein to the cysB promoter and partially reversed the ability of CysB protein to inhibit transcription initiation. These effects are in contrast to those observed in studies of positively regulated cys promoters, in which N-acetyl-L-serine stimulates binding and causes CysB protein to activate transcription initiation.

Bacterial Proteins

genetics

13694378

Trade-offs, fairness, and funding for cancer drugs: key findings from a deliberative public engagement event in British Columbia, Canada

BackgroundSpending on cancer drugs has risen dramatically in recent years compared to other areas of health care, due in part to higher prices associated with newly approved drugs and increased demand for these drugs. Addressing this situation requires making difficult trade-offs between cost, harms, and ability to benefit when using public resources, making it important for policy makers to have input from many people affected by the issue, including citizens.MethodsIn September 2014, a deliberative public engagement event was conducted in Vancouver, British Columbia (BC), on the topic of priority setting and costly cancer drugs. The aim of the study was to gain citizens’ input on the topic and have them generate recommendations that could inform cancer drug funding decisions in BC. A market research company was engaged to recruit members of the BC general public to deliberate over two weekends (four days) on how best to allocate resources for expensive cancer treatments. Participants were stratified based on the 2006 census data for BC. Participants were asked to discuss disinvestment, intravenous versus oral chemotherapy delivery, and decision governance. All sessions were audio recorded and transcribed. Transcripts were analyzed using NVivo 11 software.ResultsTwenty-four individuals participated in the event and generated 30 recommendations. Participants accepted the principle of resource scarcity and the need of governments to make difficult trade-offs when allocating health-care resources. They supported the view that cost-benefit thresholds must be set for high-cost drugs. They also expected reasonable health benefits in return for large expenditures, and supported the view that some drugs do not merit funding. Participants also wanted drug funding decisions to be made in a non-partisan and transparent way.ConclusionThe recommendations from the Vancouver deliberation can provide guidance to policy makers in BC and may be useful in challenging pricing by pharmaceutical companies.

Antineoplastic Agents

economics

217653

Design of orthogonal genetic switches based on a crosstalk map of σs, anti-σs, and promoters

Cells react to their environment through gene regulatory networks. Network integrity requires minimization of undesired crosstalk between their biomolecules. Similar constraints also limit the use of regulators when building synthetic circuits for engineering applications. Here, we mapped the promoter specificities of extracytoplasmic function (ECF) σs as well as the specificity of their interaction with anti‐σs. DNA synthesis was used to build 86 ECF σs (two from every subgroup), their promoters, and 62 anti‐σs identified from the genomes of diverse bacteria. A subset of 20 σs and promoters were found to be highly orthogonal to each other. This set can be increased by combining the −35 and −10 binding domains from different subgroups to build chimeras that target sequences unrepresented in any subgroup. The orthogonal σs, anti‐σs, and promoters were used to build synthetic genetic switches in Escherichia coli. This represents a genome‐scale resource of the properties of ECF σs and a resource for synthetic biology, where this set of well‐characterized regulatory parts will enable the construction of sophisticated gene expression programs.

Escherichia coli

genetics

20037425

Sex differences in independent factors associated with coronary artery disease

SummaryBackgroundWomen undergoing coronary angiography (CA) due to chest pain are more likely to present with less extensive coronary artery disease (CAD) than men, which might be attributed to different effects of cardiovascular risk factors on coronary atherogenesis between sexes. The aim of the present study was to evaluate sex differences in independent factors associated with obstructive and non-obstructive CAD in a large consecutive cohort of patients undergoing elective CA.MethodsData from 7819 patients (2653 women and 5184 men), including cardiovascular risk factors, clinical presentation, CAD severity and treatment decisions were analysed.ResultsWomen were older than men (65 ± 11 vs. 63 ± 11 years, p < 0.001); low-density lipoprotein cholesterol (LDL; 125 ± 38 vs. 122 ± 37 mg/dL, p < 0.001) and high-density lipoprotein cholesterol (HDL) cholesterol levels (62 ± 18 vs. 51 ± 15 mg/dL, p < 0.001) were higher in women; and smokers were more frequently men (14.4 vs. 20.1 %, p < 0.001). Men more frequently had an obstructive CAD (41.1 vs. 65.6 %, p < 0.001). Multivariable analyses revealed age, HDL cholesterol, hypercholesterolaemia, diabetes mellitus, arterial hypertension and a positive family history being associated with obstructive CAD in both sexes, whereas smoking was independently associated with obstructive CAD only in women. The association of hypercholesterolaemia with obstructive CAD was stronger in men. For non-obstructive CAD, no sex-specific associated factors could be identified.ConclusionThe impact of smoking and hypercholesterolaemia on coronary atherosclerosis is different between women and men. This might be taken into account when planning individual interventions to reduce cardiovascular risk.ZusammenfassungHintergrundBei Frauen, die sich aufgrund von Brustschmerzen einer Koronarangiographie unterziehen müssen, findet sich im Vergleich zu Männern seltener eine relevante koronare Herzkrankheit (KHK). Dies könnte auf den unterschiedlichen Einfluss kardiovaskulärer Risikofaktoren auf die KHK bei Frauen und Männern zurückzuführen sein. Das Ziel der aktuellen Studie lag darin, geschlechtsspezifische Unterschiede in unabhängig mit signifikanter und nicht-signifikanter KHK assoziierten Faktoren in einem großen konsekutiven Patientenkollektiv, bei dem eine elektive Koronarangiographie durchgeführt wurde, zu untersuchen.MethodenVon 7819 Patienten (n = 2653 Frauen, n = 5184 Männer) wurden kardiovaskuläre Risikofaktoren, die klinische Präsentation, die Schwere der KHK und therapeutische Entscheidungen analysiert.ResultateFrauen waren älter als Männer (65 ± 11 vs. 63 ± 11 Jahre, p < 0,001), LDL- (125 ± 38 vs. 122 ± 37 mg/dL, p < 0,001) und HDL-Cholesterin Werte (62 ± 18 vs. 51 ± 15 mg/dL, p < 0,001) waren höher bei Frauen, Rauchen fand sich häufiger bei Männern (14,4 vs. 20,1 %, p < 0,001). Bei Männer wurde häufiger eine signifikante KHK diagnostiziert (41,1 vs. 65,6 %, p < 0,001). In multivariablen Analysen waren das Alter, das HDL-Cholesterin, eine Hypercholesterinämie, ein Diabetes mellitus, eine arterielle Hypertonie und eine positive Familienanamnese mit dem Vorliegen einer signifikanten KHK bei beiden Geschlechtern assoziiert. Rauchen war nur bei Frauen unabhängig mit einer signifikanten KHK korreliert. Die Assoziation von Hypercholesterinämie mit einer signifikanten KHK war bei Männern stärker ausgeprägt. Für die nicht-signifikante KHK konnten keine Geschlechtsunterschiede in den unabhängig assoziierten Faktoren identifiziert werden.SchlussfolgerungDer Einfluss von Rauchen und Hypercholesterinämie auf eine KHK ist bei Frauen und Männern unterschiedlich. Dies könnte zukünftig bei der Planung von individuellen Interventionen zur Reduktion des kardiovaskulären Risikos berücksichtigt werden.

Hypertension

epidemiology

38998332

Effects of Cooling on the Response of the Snail Bursting Neuron to Acetylcholine

Abstract: The Br‐type neuron of the snail Helix pomatia, involved in neuronal regulation of various homeostatic and adaptive mechanisms, represents an interesting model for studying effects of temperature change on neuronal activity of poikilotherms. Acetylcholine induces a transient, inward dose‐dependent current in the identified Br neuron. In the work presented, we analyzed the effects of cooling on the acetylcholine‐induced inward current. The amplitude of acetylcholine‐induced inward current was markedly decreased after cooling, and the speed of the decay of acetylcholine response was decreased.

Neurons

drug effects

7756136

The Present and Future of Prostate Cancer Urine Biomarkers

In order to successfully cure patients with prostate cancer (PCa), it is important to detect the disease at an early stage. The existing clinical biomarkers for PCa are not ideal, since they cannot specifically differentiate between those patients who should be treated immediately and those who should avoid over-treatment. Current screening techniques lack specificity, and a decisive diagnosis of PCa is based on prostate biopsy. Although PCa screening is widely utilized nowadays, two thirds of the biopsies performed are still unnecessary. Thus the discovery of non-invasive PCa biomarkers remains urgent. In recent years, the utilization of urine has emerged as an attractive option for the non-invasive detection of PCa. Moreover, a great improvement in high-throughput “omic” techniques has presented considerable opportunities for the identification of new biomarkers. Herein, we will review the most significant urine biomarkers described in recent years, as well as some future prospects in that field.

Prostatic Neoplasms

urine

2611800

COMT inhibitors and liver toxicity.

This paper reviews the issue of hepatotoxicity with the use of the catechol-O-methly transferase (COMT) inhibitors tolcapone and entacapone. Neither drug caused hepatotoxicity in preclinical toxicity testing. However, in clinical trials of tolcapone, liver chemistry tests were elevated more than 3 times above the upper limit of normal in approximately 1% of patients who took the 100 mg dose and in approximately 3% of patients who took the 200 mg dose. These observations led to the recommendation that periodic monitoring of liver function be performed. Post-marketing surveillance studies noted 3 instances of acute liver failure with death after 60,000 patients had received tolcapone for a total of 40,000 patient-years. For this reason, the drug was withdrawn from the market in Europe and Canada, and a black box warning issued in the United States. In contrast, clinical trials with entacapone demonstrated no increase in liver enzymes above those observed with placebo. Further, no instances of acute liver failure or death attributed to the drug have been observed in post-marketing surveillance studies. Consequently, liver monitoring is not required with this agent. These data demonstrate that tolcapone is associated with a risk of hepatotoxicity but that no such risk has been detected with entacapone.

Liver

drug effects

32395210

EcoA and EcoE: alternatives to the EcoK family of type I restriction and modification systems of Escherichia coli.

The genes (hsd A) encoding EcoA, a restriction and modification system first identified in Escherichia coli 15T-, behave in genetic crosses as alleles of the genes (hsd K) encoding the archetypal type I restriction and modification system of E. coli K12. Nevertheless, molecular experiments have failed to detect relatedness between the A and K systems. We have cloned the hsd A genes and have identified, on the basis of DNA homology, related genes (hsd E) conferring a new specificity to a natural isolate of E. coli. We show that the overall organization of the genes encoding EcoA and EcoE closely parallels that for EcoK. Each enzyme is encoded by three genes, of which only one, hsdS, confers the specificity of DNA interaction. The three genes are in the same order as those encoding EcoK, i.e. hsdR, hsdM and hsdS and, similarly, they include a promoter between hsdR and hsdM from which the M and S genes can be transcribed. The evidence indicates that EcoA and EcoE are type I restriction and modification enzymes, but they appear to identify an alternative family to EcoK. For both families, the hsdR polypeptide is by far the largest, but the sizes of the other two polypeptides are reversed, with the smallest polypeptide of EcoK being the product of hsd S, and the smallest for the EcoA family being the product of hsdM. Physiologically, the A restriction and modification system differs from that of K and its relatives, in that A-specific methylation of unmodified DNA is particularly effective.

Escherichia coli

enzymology

24804986

Mammographic and pathologic correlation of microcalcification in disease of the breast.

Fifty-five patients with isolated microcalcification clusters and no palpable tumor of the breast were studied. All patients underwent appropriate localization biopsies and had roentgenographic, specimen roentgenographic examination of histologic confirmation that the area of microcalcification was removed. Fifteen patients proved to have a malignant lesion at biopsy and in 40 patients, it proved to be benign. Of the proved cancers, ten were noninvasive. Fourteen of the patients with cancer were free of axillary metastases. The results of the follow-up study, with a mean time of four years, revealed a 100 per cent survival rate and no recurrence of disease. Careful study of the microcalcification clusters, at preoperative mammographic examination, did not show significant differences between the malignant and benign group that could be helpful to the clinician, in predicting the nature of the lesion. Due to the reasonably high, 27 per cent, rate of malignant disease, we believe all patients with isolated microcalcification clusters at preoperative mammographic examination should have a localization biopsy.

Breast Neoplasms

diagnostic imaging

23169883

Folding DNA into Twisted and Curved Nanoscale Shapes

Stressful Self-Assembly One way to control shape during the assembly of an object is to design in stresses that cause a planned amount of deformation. Dietz et al. (p. 725; see the Perspective by Liu and Yan) designed DNA helix bundles, arranged in honeycomb lattices, in which some of the helices have insertions or deletions relative to the other helices in the bundles. The stresses help the bundles assemble into objects on the scale of tens of nanometers. Both the direction and degree of bending could be controlled, and curvatures as tight as 6 nanometers achieved. Complex shapes, such as square-toothed gears, could be created by combining multiple curved elements. Site-directed insertions and deletions of base pairs direct twist and curvature in crystal-like DNA arrays. We demonstrate the ability to engineer complex shapes that twist and curve at the nanoscale from DNA. Through programmable self-assembly, strands of DNA are directed to form a custom-shaped bundle of tightly cross-linked double helices, arrayed in parallel to their helical axes. Targeted insertions and deletions of base pairs cause the DNA bundles to develop twist of either handedness or to curve. The degree of curvature could be quantitatively controlled, and a radius of curvature as tight as 6 nanometers was achieved. We also combined multiple curved elements to build several different types of intricate nanostructures, such as a wireframe beach ball or square-toothed gears.

DNA

chemistry

45975208

Glomeruloid hemangioma –‐ a specific cutaneous marker of POEMS syndrome

In December 1998, a 49‐year‐old woman was referred by the Department of Neurology to the Dermatology Clinic for evaluation of multiple, bright red papules on her face and trunk of 6 months' duration. Two years prior to the appearance of the cutaneous eruption, she was seen for intermittent numbness and burning sensation of both hands of several months' duration and was found to have decreased sensory and motor nerve conduction velocities. Electromyography suggested axongenic demyelinating polyneuropathy. On admission for further studies in April 1996, she was noted to have generalized skin hyperpigmentation and mild splenomegaly. Laboratory studies at that time revealed anemia [hemoglobin, 9.6 g/dL (normal male, 13.5–17.5 g/dL; normal female, 12.0–16.0 g/dL)], hypothyroidism [thyroxine, 3.86 ng/dL (normal, 5.0–12.4 ng/dL); triiodothyronine, 35.4 ng/dL (normal, 62–168 ng/dL); thyroid‐stimulating hormone, 12.3 mIU/L (normal, 0.4–4.5 mIU/L)], and lambda‐type immunoglobulin A (IgA) paraprotein in the serum. A bone marrow biopsy showed marked plasma cell infiltration. POEMS (polyneuropathy, organomegaly, endocrinopathy, M‐protein, skin changes) syndrome was diagnosed at that time and she was treated with prednisolone (15–30 mg/day) and melphalan (75 mg/day). In 1997, she developed pulsatile headache and blurred vision. Increased intracranial pressure and hydrocephalus were found. Increased intracranial pressure was relieved by placement of a lumbar peritoneal shunt. In January 1998, she suffered from recurrent pleural effusion and ascites, which were treated by intermittent pleurocentesis and ascites tapping, respectively.

Skin Neoplasms

pathology

1995034

All-trans-retinoic acid-induced erythema nodosum in patients with acute promyelocytic leukemia

Erythema nodosum associated with all-trans-retinoic acid (ATRA) for acute promyelocytic leukemia (APL) is very rare. We describe four patients with classic APL who developed erythema nodosum during ATRA therapy. Fever and subsequent multiple painful erythematous nodules over extremities developed on D11, D16, D17, and D19, respectively, after ATRA therapy. The skin biopsy taken from each patient was consistent with erythema nodosum. All patients received short course of steroids. Fever subsided rapidly and the skin lesions regressed completely. All patients achieved complete remission without withdrawal of ATRA. ATRA seemed to be the most possible etiology of erythema nodosum in our patients. Short-term use of steroid is very effective in ATRA-induced erythema nodosum.

Antineoplastic Agents

adverse effects

23961894

Evaluation of the American Society of Anesthesiologists Physical Status classification system in risk assessment for plastic and reconstructive surgery patients.

BACKGROUND The American Society of Anesthesiologists Physical Status (ASA-PS) classification is a ranking system that quantifies patient health before anesthesia and surgery. Some surgical disciplines apply the ASA-PS to gauge a patient's likelihood of developing postoperative complications. OBJECTIVE In this study, the authors analyze whether ASA-PS scores can successfully predict risk for postoperative complications in plastic and reconstructive operations. METHODS The authors retrospectively reviewed the charts of 1801 patient procedures and selected for inclusion 1794 complex plastic and reconstructive operations that took place at 1 of several academic medical institutions between January 2008 and January 2012. ASA-PS scores, patient comorbidities, and postoperative complications were analyzed. Percentile data were treated with tests for proportions. Nonpercentile data were analyzed through comparison of means (t test). Low-risk (ASA 1-2) and high-risk (ASA 3+) groups were compared with simple odds ratios. RESULTS For the 1430 women and 364 men in the patient cohort (average age, 49.5 years), the overall complication rate was 27.7%. When patients with complications were compared to those without, body mass index, operation time, recent major surgery, diabetes, hypertension, renal disease, cancer, and oral contraceptive use were statistically significant. After high-risk (n = 398) and low-risk (n = 1396) groups were identified, infection, delayed wound healing, deep vein thrombosis, and overall complications had significantly increased incidence in the high risk group. Notably, deep vein thrombosis displayed the highest odds ratio (4.17) and a complication rate increase from 0.93% to 3.77%. CONCLUSIONS ASA-PS scores can be used either as substitutes for or as adjuncts to questionnaire-based risk assessment methods in plastic surgery. In addition to deducing significant findings for deep vein thrombosis incidence, ASA-PS scores hold important predictive associations for multiple non-venous thromboembolism complications, providing a broader measurement for postoperative complication risks. LEVEL OF EVIDENCE 4.

Postoperative Complications

epidemiology

13796607

Nutrient regulation of β-cell function: what do islet cell/animal studies tell us?

Diabetes mellitus is widely recognised as one of the most serious metabolic diseases worldwide, and its incidence in Asian countries is growing at an alarming rate. Type 2 diabetes (T2DM) is closely associated with age, sedentary lifestyle and poor diet. In T2DM, β-cell dysfunction will occur before hyperglycaemia develops. Excessive levels of glucose, lipid and various inflammatory factors interact at the level of the pancreatic islet to promote β-cell dysfunction. Pancreatic β-cell lines have been widely utilised since the early 1980s and have contributed a large volume of important information regarding molecular, metabolic and genetic mechanisms that regulate insulin secretion. The purpose of this review is to describe the origin and characteristics of the most commonly used β-cell lines and their contribution to discovery of fundamental regulatory processes that control insulin production and release. Pancreatic islets obtained from rodents as well as other animals have additionally provided information on the architecture and three-dimensional design of this endocrine tissue that allows precise regulation of hormone release. Understanding the nature of failure of physiologic and metabolic processes leading to insufficient insulin release and subsequent diabetes has allowed development of novel anti-diabetic therapeutics, now in common use, worldwide.

Diabetes Mellitus, Type 2

physiopathology

210925871

Age-related structural alterations of skeletal muscles and associated capillaries

Aging is associated with a progressive decline in muscle mass, strength, and quality. We have previously demonstrated the important role of the blood vasculature system in ultraviolet (UV) light-induced changes in skin and its molecular mechanisms. Whereas recent findings revealed structural alterations of the cutaneous vasculature in aged and photoaged human skin, structural changes of blood vessels in skeletal muscles with age have remained unclear. Although, facial skeletal muscles could be involved in skin-aging, here, we show—for the first time—that, in the lateral great muscle, the cross-sectional muscle fiber area and vessels size were decreased in older skin compared with that in younger skin. In the orbicularis oculi muscle, no significant interaction between age and the muscle fiber area was observed. However, a significantly decreased ratio of muscle area was indicated in older skin compared with that in younger skin. Interestingly, the pericyte-covered vessels ratio was decreased in older skin. Therefore, we found that the skeletal muscle capillary destabilizes with age. In summary, we revealed that the lateral great muscle and the orbicularis oculi muscle fibers become thinner with age due to the destabilization of skeletal muscle capillaries. Therapeutic targeting of muscle capillaries might affect the decline of skeletal muscles with age and could potentially regulate muscle/skin-aging.

Aging

physiology

8078387

Nature, nurture, and childhood overweight.

The relative importance of dietary and familial factors in determining weight in early infancy were studied in 203 5-year-old children. Their age at weaning, energy intake in infancy and at 5 years, and maternal percentage expected weight were studied in relation to their percentage expected weight. Neither the estimated energy intake in infancy nor the intake at 5 years correlated significantly with their percentage expected weight at 5 years. Overweight 5-year-olds had not been weaned earlier than normal-weight 5-year-olds. There was a significant correlation between the percentage expected weights of the mothers and those of their children at 5 years of age, although the children of overweight mothers did not have higher energy intakes than the children of underweight mothers. A familial, perhaps genetically determined, tendency to overweight seems to be more important in determining whether a child will be overweight at 5 years old than early weaning and overfeeding in infancy.

Obesity

etiology

9013686

Modulation of enantioselective metabolism and inversion of ibuprofen by xenobiotics in isolated rat hepatocytes.

R-ibuprofen undergoes chiral inversion by the formation of a coenzyme A (CoA) thioester and subsequent epimerization and hydrolysis. Using isolated rat hepatocytes, the interaction of xenobiotics with the inversion and oxidation pathways of ibuprofen enantiomers was determined from the time course of R- and S-ibuprofen and ibuprofenyl-CoA during 4-hr incubations with R- or S-ibuprofen (25 microM). By fitting a first-order model, the rate constants of the formation of ibuprofenyl-CoA (K12), oxidation of R-ibuprofen (K10), hydrolysis of ibuprofenyl-CoA (K21) and oxidation of S-ibuprofen (K30) were 1.306, 0.284, 6.858 and 0.496 hr-1, respectively. The fractional inversion of R-ibuprofen was 0.75 and the area under the curve for ibuprofenyl-CoA was 203.8 microM min. Coincubation with 50 microM of the cytochrome P450 inhibitors metyrapone and proadifen resulted in significant reductions of K10 and K30; the fractional inversion of R-ibuprofen increased to 116% and 127% and the area under the curve of ibuprofenyl-CoA to 145% and 144% of controls, respectively. Valproic acid and pivalic acid at 50 microM significantly reduced the K12 and increased the K21; the fractional inversion was unchanged but the area under the curve of ibuprofenyl-CoA was significantly reduced to 57% and 28% of controls, respectively. Valproic acid also significantly reduced K10 and K30. p-nitrobenzoic acid at 50 microM significantly increased K21 and reduced the area under the curve of ibuprofenyl-CoA to 44% of control but did not influence the fractional inversion. Selective inhibitors of ibuprofen oxidation were found to enhance significantly hepatocellular exposure to the potentially reactive ibuprofenyl-CoA intermediate.

Liver

metabolism

8369947

The Effects of Exercise in a Coronary Rehabilitation Programme

Twenty-two male and female patients who had recently suffered a myocardial infarction were randomly assigned to a treatment group who participated in a 10-week exercise-based cardiac rehabilitation programme or a routine care group who did not participate in the rehabilitation programme. Physiological and psychological function were assessed before the programme started and after it finished. Results indicated that the treatment group did not improve physiological functioning more than the control group but they did evidence statistically significant improved psychological functioning. This investigation appears to be the first attempt to assess the potential benefits of an exercise-based cardiac rehabilitation programme in Glasgow and supports the suggestion that exercise-based cardiac rehabilitation has psychological benefits.

Myocardial Infarction

rehabilitation

21760503

Increased Proportions of Sensed Presences and Occipital Spikes with 1- and 10-Msec. Point Duration of Continuous 7-HZ Transcerebral Magnetic Fields

To test the hypothesis that the numbers of “sensed presences” induced by the application of weak (1 microTesla) magnetic fields over the right hemisphere was subject to an optimal time of presentation, digital-to-analogue computer generated 7-Hz sine-waves were applied with point (“pixel”) durations of 1, 3, 5, 7, 10, or 20 msec. for 5 min. each in a sequential counterbalanced order for six subjects. The proportion of numbers of sensed presences reported along the subjects' left sides and the proportions of electroencephalographic spikes over the occipital regions were greatest when 1- or 10-msec. point durations were employed. These results indicate that the specific duration of each successive field strength composing a complex sequence should be considered when designing optimal configurations for intercalating with neurecognition.

Brain

physiology

26770698

A perspective on telmisartan and cardiovascular risk.

The angiotensin receptor blockers (ARBs) are well established as safe and effective in the treatment of arterial hypertension. Telmisartan is an ARB with potent blood-pressure lowering effects. It has a long terminal half-life of about 24 hours (the longest of any of the ARBs), which enables it to sustain blood pressure reductions in the early morning hours, after the previous morning dosing. Unlike the angiotensin-converting enzyme (ACE) inhibitors, the ARBs have not been shown to reduce mortality and morbidity in high-risk patients with coronary disease, peripheral vascular disease, cerebrovascular disease, or diabetes with cardiovascular risk factors without evidence of heart failure or low ejection fraction. Two studies, the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE-I INtolerant Subjects with Cardiovascular Disease (TRANSCEND) trial, are examining the benefits of ARBs alone and in combination with ACE inhibitors in high-risk patients.

Cardiovascular Diseases

drug therapy

37593893

Conserved repetition in the ice nucleation gene inaX from Xanthomonas campestris pv. translucens

SummaryThe nucleotide sequence was determined for the bacterial ice nucleation gene, inaX, from Xanthomonas campestris pathovar translucens X56S. Comparison of the nucleotide sequence of inaX to the previously characterized ice nucleation genes, inaZ from Pseudomonas syringae S203, inaW from Pseudomonas fluorescens MS1650, and iceE from Erwinia herbicola M1 revealed a 65.8%, 67.8%, and 68.8% homology, respectively. Within the internal, repetitive domain of the translated product of inaX are 153 consecutive octapeptide repeat units.

Bacterial Proteins

genetics

26771027

Recent developments on the integration of biologic agents with cytotoxic chemotherapy in the treatment of advanced colorectal cancer.

Colorectal cancer (CRC) is a worldwide public health problem, with nearly 800,000 new cases diagnosed each year, resulting in approximately 500,000 deaths. In the United States, it is the second leading cause of cancer mortality, and nearly 60,000 deaths will be attributed to this disease in 2008. When diagnosed as advanced/metastatic disease, CRC is traditionally associated with a poor prognosis, with 5-year survival rates in the range of 5%-8%. This survival rate has remained unchanged over the past 35-40 years. However, during the past 5 years, significant advances have been made in treatment options so that improvements in 2-year survival are now being reported, with median survival rates in the 21-24 month range in patients with metastatic disease.

Antineoplastic Agents

therapeutic use

6203246

A prospective study on patient's erectile function following transrectal ultrasound guided prostate biopsy.

OBJECTIVES This study is intended to assess variation of sexual function in 222 patient at different treatment stages of prostate cancer with the aid of a validated questionnaire in comparison with patients diagnosed with a benign lesion. The questionnaire covers the period before carrying out prostate biopsy, the disclosure of histological examination, and the recovery period. MATERIAL AND METHODS 240 patients who were to undergo trans-rectal ultrasound guided prostate biopsy due to suspected prostate cancer were consecutively and prospectively studied between January 2008 and January 2009. Patients were asked to complete an IIEF-15 questionnaire to assess sexual function during the initial consultation (T0), generally whilst they waited to be called forward for an ECG or to provide blood samples. The same questionnaire was re-administered 30 days following disclosure of results (T30) and, in all cases of confirmed malignancy, at pre-surgical admission (T pre-op). RESULTS In this study we examined results on perceived sexual function following transrectal ultrasound guided prostate biopsy for suspected neoplasia. Eighteen of the 240 consecutive patients suitable for the study were excluded due to their inability to reliably complete the IIEF-15 questionnaires provided. Histological results led to the selection of 98 patients (44.1%) with neoplastic pathology, group A, and 124 (55.8%) with benign pathology, group B. At T0 a normal level of erectile function was evident in 50 group A patients (51%) and in 50 group B patients (40.3%), while ED has been reported in 48 individuals (49%) in group A and in 74 (59.7%) in group B. At T30 we observed in group A a decrease of the mean IIEF-15 score from 53.6 to 37.8 (p = 0.0013). We observed similar results in group B, where 10/50 patients developed ED with a consequent reduction of the IIEF average score from 55.9 to 48.3 (p = 0.04). Of the 16 patients in group A who developed ED after biopsy only 2 were eligible for surgery and there were no statistical differences in the IIEF scores comparing T30 with T-pre-surgery (p = 0.36). CONCLUSIONS In this study, as previously documented in literature, no direct correlation was observed between ED in patients and the diagnosis of prostate cancer. The only seemingly correlative factor between ED and prostate cancer is biopsy itself. Further specific studies should be carried out to assess whether ED is a psychological result of an emotional stressful event or whether resulting physical damage following the biopsy procedure is to blame.

Prostatic Neoplasms

pathology

38758224

Combretastatin a-4 analogs as anticancer agents.

Combretastatin A-4 (CA-4) is one of the most potent antimitotic and antiangiogenic agents of natural origin. It has displayed potent antitumor effect in a wide variety of preclinical tumor models. Till date various CA-4 analogs have been synthesized and evaluated for anticancer activity. This review is an attempt to compile the medicinal chemistry of various synthesized CA-4 analogs.

Antineoplastic Agents

pharmacology

24146051

Low Thymic Activity and Dendritic Cell Numbers Are Associated with the Immune Response to Primary Viral Infection in Elderly Humans

Immunological competence declines progressively with age, resulting in increased susceptibility of the elderly to infection and impaired responses to vaccines. Underlying mechanisms remain largely obscure as they have been related to complex, individual systemic immune properties that are challenging to investigate. In this study, we explored age-related changes in human immunity during a primary virus infection experimentally induced by immunization with live-attenuated yellow fever (YF) vaccine. Applying detailed serology, advanced FACS analysis, and systems biology, we discovered that aged subjects developed fewer neutralizing Abs, mounted diminished YF-specific CD8+ T cell responses, and showed quantitatively and qualitatively altered YF-specific CD4+ T cell immunity. Among numerous immune signatures, low in vivo numbers of naive CD4+ recent thymic emigrants and peripheral dendritic cells correlated well with reduced acute responsiveness and altered long-term persistence of human cellular immunity to YF vaccination. Hence, we reveal in this article that essential elements of immune responses such as recent thymic emigrants and dendritic cells strongly relate to productive immunity in the elderly, providing a conceivable explanation for diminished responsiveness to vaccination with neoantigens and infection with de novo pathogens in the aged population.

Aging

immunology

37415264

Metformin is associated with a lower risk of colorectal cancer in Taiwanese patients with type 2 diabetes: A retrospective cohort analysis.

BACKGROUND The association between metformin and colorectal cancer (CRC) has rarely been investigated in Asian populations. METHODS This retrospective cohort study included patients with newly diagnosed type 2 diabetes during 1999-2005, recruited from Taiwan's National Health Insurance database. A total of 169,601 patients (original cohort: 153,270 ever-users and 16,331 never-users of metformin) and a subgroup of 1:1 propensity-score-matched pairs of 16,331 ever-users and 16,331 never-users (matched cohort) were followed up to 31 December 2011. Cox regression was constructed with the inverse probability of treatment-weighting, using propensity scores, and was used to estimate hazard ratios (HRs). RESULTS In the original cohort, the incidence of CRC was 242.9 and 480.9 per 100,000 person-years, respectively, in ever- and never-users. The overall HR [0.50, 95% confidence interval (CI): 0.45-0.56] suggested a significantly lower risk in metformin users, while compared with never-users, the HR (95% CI) for the first (<27.1 months), second (27.1-58.1 months) and third (>58.1 months) tertiles of cumulative duration of metformin therapy was 0.86 (0.76-0.98), 0.51 (0.45-0.59) and 0.26 (0.23-0.30), respectively. Analyses in the matched cohort showed similar findings with an overall HR of 0.62 (0.53-0.74), and a tertile analysis HR of 1.02 (0.81-1.28), 0.70 (0.56-0.89) and 0.32 (0.23-0.43), respectively. Re-analyses using more stringent diagnoses of CRC and cumulative duration as a continuous variable have consistently supported a protective effect with metformin use. CONCLUSION Metformin is associated with a lower frequency of CRC.

Diabetes Mellitus, Type 2

drug therapy

3718698

Evaluation of coronary plaque characteristics with coronary computed tomography angiography in patients with non-obstructive coronary artery disease: a long-term follow-up study

Aims Recent studies suggested that even non-obstructive coronary artery disease (CAD) increases major cardiovascular adverse events (MACE) rate. Aim of this study was to evaluate whether coronary computed tomography angiography (CCTA) may detect specific plaque characteristics that may affect prognosis in patients with non-obstructive CAD. Methods We enrolled 245 patients who underwent CCTA between April 2004 and April 2007 for suspected CAD and were found to have non-obstructive CAD. Positive remodelling index (PRI), low-attenuation plaque (LAP), plaque burden (PB), spotty calcification (SC), and napkin-ring sign (NRS) have been evaluated for each coronary plaque detected. Acute coronary syndrome, all-cause/cardiac death, and very late elective revascularization (vl-ER) were the endpoints of the study. Results A total of 28 events were recorded (2 STEMI, 4 NSTEMI, 6 UA, 2 cardiac deaths, 4 non-cardiac death, and 10 vl-ERs) at long-term follow-up (98 ± 20 months). When adjusted for significant clinical variables PRI > 1.4 (HR 3.31 CI 95% 1.11-9.91, P = 0.0392), LAP (HR 8.45 CI 95% 2.22-32.21, P = 0.0019), PB > 0.7 (HR 5.25 CI 95% 1.45-19.03, P = 0.0120), and NRS (HR 12.52 CI 95% 1.51-103.90, P = 0.0198) were still significantly associated with higher rate of hard cardiac events at follow-up. The Kaplan-Meyer curves confirmed lower cumulative hard cardiac events-free survival in patients presenting at least one coronary plaque with two or more high-risk characteristics when compared with patients with no lesion with more than one high-risk plaque characteristics (log-rank P < 0.0001). Conclusions High-risk plaque characteristics at CCTA (PRI > 1.4, PB > 0.7, LAP, and NRS) seem to be promising for risk stratification of patients with non-obstructive CAD.

Myocardial Infarction

diagnostic imaging

25386389

Simulating structural and thermodynamic properties of carcinogen-damaged DNA.

A pair of stereoisomeric covalent adducts to guanine in double-stranded DNA, derived from the reaction of mutagenic and tumorigenic metabolites of benzo[a]pyrene, have been well characterized structurally and thermodynamically. Both high-resolution NMR solution structures and an array of thermodynamic data are available for these 10S (+)- and 10R (-)-trans-anti -[BP]-N(2)-dG adducts in double-stranded deoxyoligonucleotides. The availability of experimentally well-characterized duplexes containing these two stereoisomeric guanine adducts provides an opportunity for evaluating the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method for computing thermodynamic properties from molecular dynamics ensembles. We have carried out 3-ns molecular dynamics simulations, using NMR solution structures as the starting models for the 10S (+)- and 10R (-)-trans-anti-dG adducts in a DNA duplex 11-mer using AMBER 6.0. We employed the MM-PBSA method to compute the free energies, enthalpies, and entropies of the two adducts. Our complete thermodynamic analysis agrees quite well with the full experimental thermodynamic characterization of these adducts, showing essentially equal stabilities of the two adducts. We also calculated the nuclear Overhauser effect (NOE) distances from the molecular dynamics trajectories, and compared them against the experimental NMR-derived NOE distances. Our results showed that the simulated structures are in good agreement with the NMR experimental NOE data. Furthermore, the molecular dynamics simulations provided new structural and biological insights. Specifically, the puzzling observation that the BP aromatic ring system in the 10S (+)-trans-anti-dG adduct is more exposed to the aqueous solvent than the 10R (-)-trans-anti-dG adduct, is rationalized in terms of the adduct structures. The structural and thermodynamic features of these stereoisomeric adducts are also discussed in relation to their reported low susceptibilities to nucleotide excision repair.

DNA

chemistry

7318130

[New aspects in the diagnosis and therapy of fetal lung immaturity. Determination of the infant respiratory system compliance. Analysis of dipalmitoylphosphatidylcholine in amniotic fluid. Use of carnitine for the enhancement of lung maturation. (Clinical and experimental results)].

The surfaceactive alveolar system (surfactant) is of central importance for a normal lung function of premature and neonates. The most important substance of this system consisting of phospholipids and lecithin is Dipalmitoyl-Phosphatidyl-Cholin (DPPC) because it specially lowers the surface tension in the alveola. A lack of surfactant leeds to the respiratory distress syndrome (RDS) of newborns which today still remains the most frequent cause of death of prematures. Many different methods have been tried to get information concerning lung maturity through analysis of phospholipids in the amniotic fluid; more over strong efforts have been made to stimulate surfactant production pharmacologically in case of diagnosed fetal lung immaturity. Corticosteroids have proven to be effective for this induction and are excepted world wide; however possible adverse effects on the mother and her fetus have let to discussions about the use of corticosteroids. Therefore the effect of Carnitine on fetal lung maturation in sheep was investigated in the experimental part of this study. The clinical part was devoted to other problems.

Lung

embryology

195893012

Visualization of Bacterial Protein Complexes Labeled with Fluorescent Proteins and Nanobody Binders for STED Microscopy

In situ visualization of molecular assemblies near their macromolecular scale is a powerful tool to investigate fundamental cellular processes. Super-resolution light microscopies (SRM) overcome the diffraction limit and allow researchers to investigate molecular arrangements at the nanoscale. However, in bacterial cells, visualization of these assemblies can be challenging because of their small size and the presence of the cell wall. Thus, although conceptually promising, successful application of SRM techniques requires careful optimization in labeling biochemistry, fluorescent dye choice, bacterial biology and microscopy to gain biological insights. Here, we apply Stimulated Emission Depletion (STED) microscopy to visualize cell division proteins in bacterial cells, specifically E. coli and B. subtilis. We applied nanobodies that specifically recognize fluorescent proteins, such as GFP, mCherry2 and PAmCherry, fused to targets for STED imaging and evaluated the effect of various organic fluorescent dyes on the performance of STED in bacterial cells. We expect this research to guide scientists for in situ macromolecular visualization using STED in bacterial systems.

Bacterial Proteins

metabolism

1451331

Is the expression of kinin B(1) receptor related to intrahepatic vascular response?

UNLABELLED Bradykinin elicits an intrahepatic vascular response (IHVR) mediated by the constitutive B(2) receptor (B(2)R). The biological effects of kinins may also be mediated by the inducible B(1) receptor (B(1)R). AIM To verify if the hepatic B(1)R expression modulates IHVR to kinins. METHOD We evaluated the ability of bradykinin and B(1)R agonists to elicit an IHVR in normal rats and in those submitted to acute or chronic inflammatory stimuli, fibrosis, cirrhosis, or hepatic regeneration. RESULTS Bradykinin-induced IHVR was similar in all groups. B(1)R agonists did not elicit in any of them either a hypertensive or a hypotensive response. B(1) receptor induction was observed in all experimental groups (Western blot), except for the acute inflammatory group. CONCLUSION B(1)R hepatic expression did not modulate IHVR to kinins.

Liver

blood supply

30325705

Abuse Experiences in a Community Sample of Young Adults: Relations with Psychiatric Disorders, Sexual Risk Behaviors, and Sexually Transmitted Diseases

This study documents significant associations among lifetime abuse experiences, psychiatric diagnoses, and sexual risk behaviors in a multiethnic community sample of young men and women (N = 1803) in South Florida. Self-report data were collected via structured interviews as part of a longitudinal follow-up of a larger school-based study. Participants were grouped according to extent of lifetime abuse experiences. Cumulative lifetime abuse experiences were associated with increased risk for a broad range of individual lifetime psychiatric disorders, as well as cumulative lifetime psychiatric disorders. Both cumulative abuse experiences and cumulative psychiatric disorders were independently associated with (a) higher levels of sexual risk behaviors and (b) higher risk for lifetime sexually transmitted diseases (STDs). Implications for selective prevention of sexual risk behaviors and STDs among young adults with histories of abuse and psychiatric disorders are discussed.

Mental Disorders

epidemiology

31384904

Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels.

BACKGROUND & AIMS Long-term primary antibiotic prophylaxis of spontaneous bacterial peritonitis has been suggested to be useful in cirrhotic patients with low ascitic fluid protein levels. However, it is unlikely that all such patients need prophylactic treatment. The aim of this study was to identify the group of cirrhotic patients with low ascitic fluid protein levels at high risk of developing a first episode of spontaneous bacterial peritonitis during outpatient follow-up. METHODS One hundred nine cirrhotic patients with low ascitic fluid protein levels and without previous episodes of spontaneous bacterial peritonitis were followed up in an outpatient clinic. RESULTS Twenty-eight patients developed a first spontaneous bacterial peritonitis episode. In the multivariate analysis, serum bilirubin level (>3.2 mg /dL) and platelet count (<98.000/mm(3)) independently correlated with the risk of developing the first spontaneous bacterial peritonitis (P < 0.01 and P < 0.05, respectively). According to the median relative risk coefficient, a low-risk group (relative risk <1.09) and a high-risk group (relative risk >1.09) were established. The probability of developing a first spontaneous bacterial peritonitis episode at 1-year follow-up was significantly higher in the high risk-group (low-risk group, 23.6%; high-risk group, 55%; P < 0.01) as a consequence of a higher probability of the first community-acquired episode (13.7% vs. 47.6%, respectively, P < 0.01). One-year probability of survival was significantly lower in the high-risk group (low-risk group, 57.6%; high-risk group, 38%, P < 0.05). CONCLUSIONS Cirrhotic patients with low ascitic fluid protein levels (</=1 g /dL) and high bilirubin level and/or low platelet count are at high risk of developing a first episode of spontaneous bacterial peritonitis during long-term follow-up.

Proteins

analysis

30649839

16q22.1 microdeletion detected by array-CGH in a family with mental retardation and lobular breast cancer.

We describe the case of a boy with psychomotor delay and dysmorphic features, with a germline 16q22.1 microdeletion identified by array-CGH. The deletion spans 0.24Mb and encompasses three genes (ZFP90, CDH3 and CDH1). The deletion has been demonstrated to be inherited from his mother who was affected by lobular breast cancer (LBC) without any other apparently phenotypic features. We suppose that the microdeletion, in particular ZFP90 which is cerebrally expressed, is causative for the boy's phenotype. Mental retardation in the affected boy can recognize several mechanisms such as variable expressivity, non-penetrance, multifactorial/polygenic inheritance, recessive inheritance, a second rearrangement event and epigenetics. Furthermore, we suggest that the deletion of the CDH1, a tumor suppressor gene, involved in hereditary diffuse gastric cancer (HDGC) and LBC predisposed the mother to the carcinoma.

Breast Neoplasms

genetics

209262394

TREATMENT OF SEVERE HYPERTENSION WITH GUANETHIDINE

S FROM MEDICA,L LITERATl'REOrthopredlc Surgery 710 Prediatrics 711

Hypertension

therapy

2375540

Purification of a 15-kDa cdk4- and cdk5-binding protein.

Yeasts p13suc1/p18CKS and their human homologues, p9CKShs1/p9CKShs2, strongly interact with p34cdc2 and p34cdk2. While attempting to purify the starfish oocyte p13suc1 homologue, we discovered a 15-kDa protein cross-reactive with anti-p9CKShs2/anti-p13suc1 antibodies. p15cdk-BP-Sepharose binds an anti-PSTAIRE cross-reactive protein of 33 kDa when loaded with starfish oocyte extracts. The p15cdk-BP-bound "PSTAIRE signal" is part of a 250-kDa complex distinct from p34cdc2/cyclin B. p15cdk-BP-Sepharose beads retain a kinase phosphorylating HMG I/Y, P1, and myelin basic protein (among 24 substrates tested). Major cdc2 kinase substrates are not phosphorylated by the p15cdk-BP-bound kinase. Phosphopeptide maps of P1 phosphorylated by the p15cdk-BP-bound kinase, p34cdc2/cyclin B, p 33cdk5/p25, and casein kinase 2 showed that these kinases phosphorylate P1 on different sites. Phosphopeptide maps of P1 phosphorylated by the p15cdk-BP-bound starfish kinase and p15cdk-BP-bound human p34cdk4/cyclin D are largely coincident. To investigate the nature of the p15cdk-BP-bound kinase, extracts of mammalian tissues and cells were loaded on p9CKShs1- and p15cdk-BP-Sepharose and the bound proteins were analyzed using specific anti-cdk antibodies. cdc2 and cdk2 bind to p9CKShs1-Sepharose, but not to p15cdk-BP. cdk4 and cdk5 bind to p15cdk-BP-Sepharose, but not to p9CKShs1-Sepharose. We conclude that p15cdk-BP specifically binds the cdk4/cyclin D and cdk5 kinases and, along with p13suc1 and p9CKShs, may be part of a larger family of cdk-binding proteins.

Proteins

isolation & purification

27111730

Detection and Assessment of Pyelectasis in the Fetus: Relationship to Postnatal Renal Function

Objective To assess the relationship between fetal pyelectasis determined by ultrasonography and postnatal renal function. Methods We first established normal values for anteroposterior, transverse, and longitudinal diameters of the renal pelvis sonographically in 68 normal fetuses at 30-40 weeks' gestation. We also evaluated prospectively the relationship between the severity of pyelectasis (diameter at least two standard deviations above the normal mean) in 36 fetuses at 30-40 weeks' gestation and postnatal renal function. Fetal renal function also was evaluated through measurement of the hourly urine production rate, whereas postnatal renal function was assessed by technetium 99m-diethylenetriamine penta-acetic acid renography and excretory urography. Results Fetal pyelectasis was diagnosed when renal pelvic diameters were at least 8 mm (anteroposterior), 11 mm (transverse), and 14 mm (longitudinal), all upper limits of normal diameters of 68 normal fetuses as determined in the first part of the study. Pyelectasis was associated with a normal urine production rate in all fetuses, but in six fetuses it was associated with a normal urine production rate in all fetuses, but in six fetuses it was associated with a progressive deterioration of renal function within the 1st month of life, requiring neonatal surgery. In the other 30 fetuses with pyelectasis, who did not require neonatal surgery, pyelectasis decreased gradually or totally disappeared within 2 years. Renal pelvic anteroposterior, transverse, and longitudinal pelvic diameters were at least 20, 25, and 26 mm, respectively, during late fetal life in those neonates at the time of corrective surgery. The mean anteroposterior diameter in those fetuses who did not require surgery at infancy (11 ± 6 mm) was significantly less than in those requiring surgery (33 ± 14 mm, P < .01). Likewise, the transverse diameters were 17 ± 10 mm and 38 ± 16 mm (P < .01) and the longitudinal diameters were 20 ± 10 mm and 48 ± 22 mm (P < .01) Conclusion Neonatal surgery is recommended when the anteroposterior, transverse, and longitudinal renal pelvic diameters during the prenatal period are at least 20, 25, and 26 mm, respectively. Surgery is not necessary when the diameters are less than 20 mm.

Kidney

physiology

30634005

A triangular conditioning voltage wave does not influence spontaneous neuronal activity in the rat striatum

A triangular potential wave applied shortly before each measuring triple pulse has been used in in vivo voltammetric experiments to ensure the maintenance of a high level of stability and sensitivity in the carbon fiber electrode. To investigate whether a triangular wave (0- +/- 1500 mV, 10 V/s slope) and a consecutive triple pulse affect spontaneous neuronal firing, extracellular recordings were made in the rat striatum at a distance of about 200-300 microns from the carbon fiber electrode while these potentials were being delivered. No significant change in the rate of spontaneous firing was found. A triangular pulse has proven to be very effective in lengthening the measurement lifetime of the carbon fiber electrode without interfering with the spontaneous activity of striatal neurons.

Neurons

physiology