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2961883

Techniques for studying hepatic metabolismin vivo

SummaryTechniques for studying metabolic eventsin vivo in patients with inborn errors are reviewed. Loading or provocation tests that have been used widely are insensitive and frequently non-specific. Compounds labelled with stable isotopes can be used to study enzyme kinetics and substrate turnover, providing more detailed and specific information. Intracellular events may be studied using nuclear magnetic resonance spectroscopy.The results using these techniques to study patients with selected inborn errors are discussed, namely phenylketonuria, glycogen storage disease type I and propionic acidaemia.

Liver

metabolism

51922405

Enhancing value and lowering costs of care: a qualitative exploration of a randomized linkage to care intervention in South Africa

ABSTRACT While interventions to improve HIV linkage and retention in care exist, none have demonstrated results sufficient to reach UNAIDS 90-90-90 goals. We explored values and costs of seeking clinical care through testing three strategies to improve linkage to care: Point of care CD4 testing alone (POC-CD4), POC-CD4 combined with transportation support and combined with care facilitation. We conducted in-depth interviews with participants and transcribed audio-recordings of care facilitation sessions. Participants described values and costs enhanced or addressed by the three interventions. Psychosocial support provided through the care facilitation intervention appeared salient. Participants named other values and costs of seeking care unrelated to the intervention, such as encouragement from healthcare workers and aversion to lifelong treatment. Combined with the quantitative results of this trial, these findings may point to why the care facilitation arm was successful but not the POC-CD4 only or transportation arms. It also provides guidance for future interventions.

HIV Infections

drug therapy

16510578

Clinical utility of RD1, RD9 and hsp65 based PCR assay for the identification of BCG in vaccinated children

BackgroundMycobacterium bovis Bacille Calmette-Guérin (BCG) vaccine is widely administered to prevent tuberculosis. Vaccine complications are rare. However, when BCG-related adverse reactions arise there is a need to rapidly and reliably identify BCG from other members of the Mycobacterium tuberculosis complex (TBC). PCR assays based on the detection of the regions of difference (RD), in particular RD1 and RD9, have been invaluable in the identification of BCG. Prior to this study, specimens were identified through HPLC analysis at a local reference laboratory taking up to 2 weeks for a result. We sought to expedite the identification process by validating a RD1, RD9 and hsp65 PCR assay for the identification and differentiation of BCG from TBC.FindingsIn last past 3 years, we validated the RD1, RD9 and hsp65 PCR assay for 16 mycobacterial isolates obtained from children who had experienced adverse reactions to BCG vaccination. In these cases, the clinician required a definitive identification of the isolate. The RD1 and RD9 PCR profiles indicated that all 16 isolates were BCG whilst amplification of the hsp65 target functioned as a PCR positive control. When tested against clinical M. tuberculosis (MTB), reference and non-tuberculous mycobacteria the PCR assay demonstrated 100% sensitivity and specificity.ConclusionsThe RD1, RD9 and hsp65 PCR assay is a useful tool for the rapid and reliable identification of BCG. Its ease of use has allowed it to be implemented in our clinical microbiology laboratory.

Bacterial Proteins

genetics

46430120

Action of Choline on Lipid Phosphorylation in the Kidney, Heart and Aorta.∗

Summary 1. The lipid phosphorylation affects of a single dose of choline were compared in rats maintained on low protein-high fat diet or similar diet supplemented with methyl acceptor, guanidoacetic acid. 2. Administration of a single dose of choline stimulated lipid phosphorylation in the kidney. heart and aorta.

Kidney

metabolism

220923612

Neuroprotective effects of melatonin against neurotoxicity induced by intranasal sodium dimethyldithiocarbamate administration in mice.

Exposure to fungicide ziram (zinc dimethyldithiocarbamate) has been associated with increased incidence of Parkinson's disease (PD). We recently demonstrated that the intranasal (i.n.) administration of sodium dimethyldithiocarbamate (NaDMDC, a more soluble salt than ziram) induces PD-like behavioral and neurochemical alterations in mice. We now investigated the putative neuroprotective effects of melatonin on behavioral and neurochemical deficits induced by i.n. NaDMDC. Melatonin treatment (3, 10 or 30 mg/kg, i.p.) was given 1 h before NaDMDC administration (1 mg/nostril) during 4 consecutive days and we evaluated early (up to 7 days) and late (up to 35 days) NaDMDC-induced behavioral and neurochemical alterations. Melatonin treatment protected against early motor and general neurological impairments observed in the open field and neurological score of severity, respectively, and late deficits in rotarod test. Melatonin prevented the NaDMDC-induced alterations in the striatal tyrosine hydroxylase immunocontent. Melatonin also protected against increased levels of oxidative stress markers (4-hydroxynonenal and 3-nitrotyrosine) in the striatum, as well as the NaDMDC-induced increase of 4-hydroxynonenal and TNF, markers of oxidative stress and inflammation, respectively, in the olfactory bulb. These results further detail the mechanisms underlying NaDMDC toxicity and demonstrate the neuroprotective effects of melatonin against the neuronal damage induced by NaDMDC.

Brain

drug effects

53212619

Role of calcium in reactive oxygen species-induced apoptosis in Candida albicans: an antifungal mechanism of antimicrobial peptide, PMAP-23

Abstract PMAP-23 (RIIDLLWRVRRPQKPKFVTVWVR-NH2) is an antimicrobial peptide (AMP) derived from porcine myeloid. Membrane disruption is thought to underpin the anticandidal activity of PMAP-23. However, many AMPs act via mechanisms other than simple membrane permeabilisation. Here, we investigated the anticandidal mechanism of PMAP-23 at low concentrations. Membrane disruption and depolarisation and rapid K+ efflux were observed in Candida albicans cells treated with 5 µM PMAP-23. In contrast, 2.5 µM PMAP-23 caused membrane depolarisation and K+ efflux without membrane disruption. The lower PMAP-23 concentration increased cytosolic and mitochondrial Ca2+ levels. Disruption of Ca2+ homeostasis altered the NAD+/NADH ratio and resulted in reactive oxygen species (ROS) accumulation and glutathione oxidation. PMAP-23 treatment also stimulated apoptosis, as evidenced by metacaspase activation, DNA fragmentation, and phosphatidylserine externalisation. Pretreatment with the mitochondrial Ca2+ uptake inhibitor (ruthenium red) or ROS scavenger (N-acetylcysteine) attenuated these apoptotic events. Our results suggest that PMAP-23 induces apoptosis as antifungal mechanism, and mitochondrial Ca2+-induced ROS is major factor to trigger the apoptosis. Thus, the anticandidal activity of PMAP-23 is not based solely on disruption of biological membranes but also involves induction of apoptosis via mitochondrial Ca2+-dependent ROS. PMAP-23 mode of action sheds new light on the antifungal mechanism of antimicrobial peptides, supporting the role of Ca2+ and ROS in apoptosis regulation.

Calcium

metabolism

25390093

Hepatic intra-arterial infusion of yttrium-90 microspheres in the treatment of recurrent hepatocellular carcinoma after liver transplantation: a case report.

Hepatocellular carcinoma (HCC) recurs with a reported frequency of 12%-18% after liver transplantation. Recurrence is associated with a mortality rate exceeding 75%. Approximately one-third of recurrences develop in the transplanted liver and are therefore amenable to local therapy. A variety of treatment modalities have been reported including resection, transarterial chemo-embolization (TACE), radiofrequency ablation (RFA), ethanol ablation, cryoablation, and external beam irradiation. Goals of treatment are tumor control and the minimization of toxic effect to functional parenchyma. Efficacy of treatment is mitigated by the need for ongoing immunosuppression. Yttrium-90 microspheres have been used as a treatment modality both for primary HCC and for pre-transplant management of HCC with promising results. Twenty-two months after liver transplantation for hepatitis C cirrhosis complicated by HCC, a 42-year old man developed recurrence of HCC in his transplant allograft. Treatment of multiple right lobe lesions with anatomic resection and adjuvant chemotherapy was unsuccessful. Multifocal recurrence in the remaining liver allograft was treated with hepatic intra-arterial infusion of yttrium-90 microspheres (SIR-Spheres, Sirtex Medical Inc., Lake Forest, IL, USA). Efficacy was demonstrated by tumor necrosis on imaging and a decrease in alpha-fetoprotein (AFP) level. There were no adverse consequences of initial treatment.

Liver Neoplasms

radiotherapy

23002041

Increased power spectral density in resting-state pain-related brain networks in fibromyalgia

Summary Higher power spectral density in patients with fibromyalgia may implicate the enhanced resting‐state baseline neural activity in several brain regions associated with pain processing. ABSTRACT Fibromyalgia (FM), characterized by chronic widespread pain, is known to be associated with heightened responses to painful stimuli and atypical resting‐state functional connectivity among pain‐related regions of the brain. Previous studies of FM using resting‐state functional magnetic resonance imaging (rs‐fMRI) have focused on intrinsic functional connectivity, which maps the spatial distribution of temporal correlations among spontaneous low‐frequency fluctuation in functional MRI (fMRI) resting‐state data. In the current study, using rs‐fMRI data in the frequency domain, we investigated the possible alteration of power spectral density (PSD) of low‐frequency fluctuation in brain regions associated with central pain processing in patients with FM. rsfMRI data were obtained from 19 patients with FM and 20 age‐matched healthy female control subjects. For each subject, the PSDs for each brain region identified from functional connectivity maps were computed for the frequency band of 0.01 to 0.25 Hz. For each group, the average PSD was determined for each brain region and a 2‐sample t test was performed to determine the difference in power between the 2 groups. According to the results, patients with FM exhibited significantly increased frequency power in the primary somatosensory cortex (S1), supplementary motor area (SMA), dorsolateral prefrontal cortex, and amygdala. In patients with FM, the increase in PSD did not show an association with depression or anxiety. Therefore, our findings of atypical increased frequency power during the resting state in pain‐related brain regions may implicate the enhanced resting‐state baseline neural activity in several brain regions associated with pain processing in FM.

Brain

pathology

19319042

Processing of carnitine octanoyltransferase pre-mRNAs by cis and trans-splicing.

Trans-splicing is a mechanism by which two pre-mRNAs are processed to produce a mature transcript that contains exons from both precursors. This process has been described mostly in trypanosoma, nematodes, plant/algal chloroplasts and plant mitochondria [Bonen et al. (1993) FASEB J. 7, 40-46]. Our studies clearly demonstrate that a trans-splicing reaction occurs in the processing of the carnitine octanoyltransferase (COT) gene in rat liver. Three different mature transcripts of COT have been found in vivo, the canonical cis-spliced mRNA and two trans-spliced transcripts, in which either exon 2 or exons 2 and 3 are repeated. Splicing experiments in vitro also indicate the capacity of exon 2 to act either as a donor or as an acceptor of splicing, allowing the trans-splicing reactions to occur.

Liver

enzymology

40612727

Dense breast notification: anatomy, imaging, and patient awareness.

PURPOSE To review the current literature pertaining to dense breast anatomy, imaging considerations, and patient notification laws. METHODS The literature for this review was obtained by searching for peer-reviewed articles about breast density and breast density notification for the years 2009 to 2012 using Google Scholar. RESULTS The research regarding dense breast anatomy, imaging options related to dense breasts, and notification laws yields important considerations for patients, physicians, and imaging science professionals performing the procedures. DISCUSSION Dense breast anatomy can hinder the accuracy of screening mammography. Breast density notification laws inform patients about the density level of their breasts and introduce them to additional imaging options. The laws raise questions about whether notification is necessary and beneficial or whether it leads to increased radiation exposure, health care costs, and stress to the patient. CONCLUSION Dense breast notification laws serve to inform patients about their anatomy and provide them with the knowledge to make informed health care decisions.

Breast Neoplasms

diagnostic imaging

24086794

In vitro response of human pathological hematopoietic cells to cladribine.

The influence of cladribine (2-chloro-2'-deoxyadenosine, CdA) on in vitro response of human acute lymphoblastic leukemia MOLT-4 cells, human histiocytic lymphoma U-937 cells, and human promyelocytic leukemia HL-60 cells, was determined using the MTT spectrophotometric and Beckman Coulter methods. Cell viability, cell volume and count were compared 24h and 48h after cladribine application at four concentrations--50 nM, 100 nM, 250 nM, and 500 nM. Different patterns of temporary changes in the viability, volume and count of pathological hematopoietic cells exposed to the action of CdA were found. The effects of CdA on MOLT-4, U-937, and HL-60 cells were dependent on the agent tested and its concentration, the time intervals after agent application, and the cell line used. The various in vitro cytotoxic activities of CdA against the three human pathological hematopoietic cell lines were shown.

Antineoplastic Agents

pharmacology

33576190

Leptin, but not adiponectin, predicts stroke in males

Objective.  To test whether leptin and adiponectin are risk markers for a first‐ever stroke.

Proteins

analysis

36214796

Cloning and expression of secreted antigens of Clostridium difficile in Escherichia coli

The feasibility of the cloning and expression of Clostridium difficile antigens in Escherichia coli was investigated. The expression of a limited number of cloned clostridial antigens under the control of clostridial promoter elements in E. coli was observed.

Escherichia coli

genetics

205956810

Difference of lower airway microbiome in bilateral protected specimen brush between lung cancer patients with unilateral lobar masses and control subjects

The functional role of respiratory microbiota has attracted an accumulating attention recently. However, the role of respiratory microbiome in lung carcinogenesis is mostly unknown. Our study aimed to characterize and compare bilateral lower airway microbiome of lung cancer patients with unilateral lobar masses and control subjects. Protected bronchial specimen brushing samples were collected from 24 lung cancer patients with unilateral lobar masses (paired samples from cancerous site and the contralateral noncancerous site) and 18 healthy controls undergoing bronchoscopies and further analyzed by 16S rRNA amplicon sequencing. As results, significant decreases in microbial diversity were observed in patients with lung cancer in comparison to the controls, alpha diversity steadily declined from healthy site to noncancerous to cancerous site. Genus Streptococcus was significantly more abundant in cancer cases than the controls, while Staphylococcus was more abundant in the controls. The area under the curve of genus Streptococcus used to predict lung cancer was 0.693 (sensitivity = 87.5%, specificity = 55.6%). The abundance of genus Streptococcus and Neisseria displayed an increasing trend whereas Staphylococcus and Dialister gradually declined from healthy to noncancerous to cancerous site. Collectively, lung cancer‐associated microbiota profile is distinct from that found in healthy controls, and the altered cancer‐associated microbiota is not restricted to tumor tissue. The genus Streptococcus was abundant in lung cancer patients and exhibited moderate classification potential. The gradual microbiota profile shift from healthy site to noncancerous to paired cancerous site suggested a change of the microenvironment associated with the development of lung cancer.

Lung Neoplasms

microbiology

41531555

[Risk factors associated with human immunodeficiency virus in men deprived of their liberty in Merida, Yucatan, Mexico].

A case control study was conducted to know risk factors associated to HIV infection in Yucatan, Mexico jails. Repeated imprisonment, having more than eleven intercourses couples and having sex with other men were statistically related to HIV infection. Tattooing and intravenous drugs abuse were no significant risk factors.

HIV Infections

transmission

30051403

Rupture of the interventricular septum due to myocardial infarction: report of two cases.

Excerpt Septal myocardial infarction has been described in the literature at great length, together with injection studies of the coronary arteries in the infarcted areas, and electrocardiographic ...

Myocardial Infarction

complications

11307775

Age and gender-related differences in mitral cells of olfactory bulb.

OBJECTIVE To investigate the age and gender-related differences in mitral cells of the human cadaveric olfactory bulbs. STUDY DESIGN A cross-sectional study. PLACE AND DURATION OF STUDY The study was conducted in the Department of Anatomy, University of Health Sciences, Lahore, from August 2005 to July 2007. METHODOLOGY Sixty olfactory bulbs, 30 each from male and female (age 20-76 years) human cadavers divided into six groups of age and gender-wise were collected from the mortuary of the King Edward Medical University, Lahore. Mitral cells were counted and their diameter was calculated from 10 microm thick cresyl violet stained histological sections. Statistical analysis was done using ANOVA for age-related differences and independent t-test for gender-related differences. RESULTS There was significant reduction in the number of mitral cells and diameter of their nuclei with age. There was significant decrease in the number of mitral cells in males, between groups I and II (p < 0.001); II and III (p < 0.001); and I and III (p < 0.001); statistically significant decrease also occurred in females, between groups IV and V (p < 0.001); V and VI (p < 0.001); and IV and VI (p < 0.001). In most cases, the distance between individual mitral cells was seen to be much greater than in younger group. In group VI, few mitral cells were observed in the cell layer. There was also significant decrease in the diameter of mitral cell nuclei in males, between groups I and III (p < 0.001); and II and III (p < 0.010); in females, between groups IV and VI (p < 0.001); and V and VI (p < 0.001). No gender-related differences were observed. CONCLUSION The number of mitral cells and diameter of their nuclei decreased with advancing age.

Neurons

cytology

220270836

Postoperative complications of pulmonary resection.

Thoracic surgery has seen a resurgence in recent years with increasing numbers of cases taken on since the mid-2000s. There has been a paradigm shift in how we manage lung cancer with more emphasis on surgical resection, and this has been aided by minimally invasive video-assisted thoracic surgery (VATS) techniques. As a result, the prevalence of postoperative findings and complications is also increasing, and it is increasingly important for the general radiologist to recognise and diagnose these conditions as thoracic surgical patients may present acutely to non-thoracic surgical institutions. This review will cover both the early and late complications following a variety of lung resection surgeries.

Postoperative Complications

diagnostic imaging

7777055

Neurotensin Broadly Recruits Inhibition via White Matter Neurons in the Mouse Cerebral Cortex: Synaptic Mechanisms for Decorrelation

The neuropeptide, neurotensin (NT), inhibits UP state generation in the cerebral cortex and temporally restricts the response to thalamic input, likely by a generalized increase in inhibition. To investigate the cellular and circuit substrate(s) for how a neuropeptide can shift the balance between cortical excitation and inhibition, we performed whole-cell recordings on slice preparations from mice expressing enhanced green fluorescent protein under control of the promoter for the homeobox gene, lhx6 (lhx6-EGFP mice). These mice identify the 2 largest classes of cortical interneurons; FS and low-threshold-spiking inhibitory neurons. In the presence of NT, both types of lhx6-EGFP neurons were excited through a direct, Na+-dependent depolarization, and through an increase in synaptic excitation. Paired recordings identified cortical white matter (WM) neurons as a source of this excitatory input, which was strengthened in the presence of NT. NT-driven increased synaptic input caused a functional decorrelation of gap junction transmission between lhx6-EGFP neuron pairs. Finally, the synaptic transmission between pyramidal cells and lhx6-EGFP neurons was modulated by addition of NT in favor of stronger inhibition and weaker excitation. These findings demonstrate the existence and functional consequences of an intracortical WM neuron projection, and suggest mechanisms underlying NT-induced promotion of wakefulness.

Neurons

physiology

2694965

The close linkage between the elasticity modulus measured by real-time mapping shear wave elastography and the presence of hepatocellular carcinoma in patients with a sustained virological response to interferon for chronic hepatitis C

PurposeSome patients develop hepatocellular carcinoma (HCC) after sustained virological response (SVR) to interferon therapy for chronic hepatitis C (CH-C). The aim of this study was to examine the linkage between liver elasticity and the presence/absence of HCC in patients after SVR.MethodsWe enrolled 42 patients who underwent real-time mapping shear wave elastography (SWE) after SVR to interferon therapy for CH-C. Of the 42 patients, six had HCC and 36 did not. We retrospectively compared the elasticity modulus and other clinical parameters between patients with and without HCC.ResultsElasticity modulus measured by SWE, age, and serum albumin was significantly different between patients with and without HCC. Age, Fibrosis-4 index, serum gamma-globulin, total protein, and albumin levels were significantly correlated with the elasticity modulus. Areas under receiver operating characteristic curves of elasticity modulus, gamma-globulin, and age for the presence of HCC were 0.963, 0.888, and 0.778, respectively. In patients with an elasticity modulus ≥6.5 kPa, both sensitivity and specificity for the presence of HCC were 83.3 %.ConclusionThe study demonstrated the close linkage between the elasticity modulus measured by SWE and the presence of HCC in patients after SVR.

Liver Neoplasms

diagnostic imaging

2293030

Swyer-James-Macleod syndrome: A case with a baseline normal chest radiograph

Development of Swyer-James-Macleod syndrome in a child which can be directly attributed to an adenoviral pneumonia is presented. The case is remarkable as there is a baseline normal chest x-ray immediately prior to the pneumonia and subsequent development of the hyperlucent, hypoplastic lung.

Lung

diagnostic imaging

58599201

Patterns of body mass index milestones in early life and cardiometabolic risk in early adolescence.

BACKGROUND Few studies have examined the independent and combined relationships of body mass index (BMI) peak and rebound with adiposity, insulin resistance and metabolic risk later in life. We used data from Project Viva, a well-characterized birth cohort from Boston with repeated measures of BMI, to help fill this gap. METHODS Among 1681 children with BMI data from birth to mid childhood, we fitted individual BMI trajectories using mixed-effects models with natural cubic splines and estimated age, and magnitude of BMI, at peak (in infancy) and rebound (in early childhood). We obtained cardiometabolic measures of the children in early adolescence (median 12.9 years) and analysed their associations with the BMI parameters. RESULTS After adjusting for potential confounders, age and magnitude at infancy BMI peak were associated with greater adolescent adiposity, and earlier adiposity rebound was strongly associated with greater adiposity, insulin resistance and metabolic risk score independently of BMI peak. Children with a normal timing of BMI peak plus early rebound had an adverse cardiometabolic profile, characterized by higher fat mass index {β 2.2 kg/m2 [95% confidence interval (CI) 1.6, 2.9]}, trunk fat mass index [1.1 kg/m2 (0.8, 1.5)], insulin resistance [0.2 units (0.04, 0.4)] and metabolic risk score [0.4 units (0.2, 0.5)] compared with children with a normal BMI peak and a normal rebound pattern. Children without a BMI peak (no decline in BMI after the rise in infancy) also had adverse adolescent metabolic profiles. CONCLUSIONS Early age at BMI rebound is a strong risk factor for cardiometabolic risk, independent of BMI peak. Children with a normal peak-early rebound pattern, or without any BMI decline following infancy, are at greatest risk of adverse cardiometabolic profile in adolescence. Routine monitoring of BMI may help to identify children who are at greatest risk of developing an adverse cardiometabolic profile in later life and who may be targeted for preventive interventions.

Cardiovascular Diseases

epidemiology

11908089

Novel macrocyclic antibiotics: megovalicins A, B, C, D, G and H. II. Isolation and chemical structures of megovalicins.

Myxococcus flavescens AJ12298 was found to produce the complex of macrocyclic antibiotics named megovalicins. The physico-chemical studies revealed that megovalicins C and B were identical to myxovirescin A1 and antibiotic M-230B, respectively, and that megovalicins A, D, G and H were closely related new antibiotics.

Anti-Bacterial Agents

isolation & purification

21523804

Clinical significance of cerebral white matter lesions in older Asians with suspected dementia.

BACKGROUND cerebral white matter lesions are commonly seen on neuroimaging in older people and have been associated with clinical features such as gait abnormalities, urinary incontinence and depression. The significance of cerebral white matter lesions in older people with dementia remains uncertain. OBJECTIVES to study the association between cerebral white matter lesions and the presence or absence of dementia in a group of elderly Asian patients; and to determine the clinical significance of cerebral white matter lesions in patients who are diagnosed to have dementia in terms of associated clinical features and the impact of cerebral white matter lesions on cognitive status. METHODS for the first objective, the records of 141 older people of Asian ethnicity presenting to a memory clinic for the evaluation of suspected dementia were reviewed to compare the prevalence of cerebral white matter lesions in patients who did not fulfil the criteria for dementia, patients diagnosed to have Alzheimer's disease and patients diagnosed to have vascular dementia. For the second objective, 115 of these patients who were diagnosed to have dementia were studied to determine if demented patients with cerebral white matter lesions were more likely to have urinary incontinence, Parkinsonism, depression and greater severity of dementia. In addition, a comparison was made between demented patients with cerebral white matter lesions and those without cerebral white matter lesions in terms of psychometric assessment scores. RESULTS cerebral white matter lesions were more common in Asian patients with vascular dementia. Demented patients with cerebral white matter lesions were also found to have more severe dementia and greater functional disability. CONCLUSION cerebral white matter lesions are common, and are associated with greater functional disability in elderly Asian patients with dementia.

Brain

pathology

45118397

A human serotonin 1D receptor variant (5HT1D beta) encoded by an intronless gene on chromosome 6.

An intronless gene encoding a serotonin receptor (5HT1D beta) has been cloned and functionally expressed in mammalian fibroblast cultures. Based on the deduced amino acid sequence, the gene encodes a 390-amino acid protein displaying considerable homology, within putative transmembrane domains (approximately 75% identity) to the canine and human 5HT1D receptors. Membranes prepared from CHO cells stably expressing the receptor bound [3H]serotonin with high affinity (Kd 4 nM) and displayed a pharmacological profile consistent, but not identical, with that of the characterized serotonin 5HT1D receptor. Most notably, metergoline and serotonergic piperazine derivatives, as a group, display 3- to 8-fold lower affinity for the 5HT1D beta receptor than for the 5HT1D receptor, whereas both receptors display similar affinities for tryptamine derivatives, including the antimigraine drug sumatriptan. Northern blot analysis revealed an mRNA of approximately 5.5 kilobases expressed in human and monkey frontal cortex, medulla, striatum, hippocampus and amygdala but not in cerebellum, olfactory tubercle, and pituitary. The 5HT1D beta gene maps to human chromosome 6. The existence of multiple neuronal 5HT1D-like receptors may help account for some of the complexities associated with [3H]serotonin binding patterns in native membranes.

Brain

physiology

2943846

Reaction of rat hepatic glucokinase with substrate-related and other alkylating agents.

The reaction of rat hepatic glucokinase with a variety of alkylating agents has been investigated. The substrate-related alkylating agents N-bromoacetylglucosamine, N(-N-bromoacetyl)glycylglucosamine and N-(N-bromoacetyl)-6-aminohexanoylglucosamine are all good competitive inhibitors, with respect to glucose, of the glucokinase reaction. However, whereas N-bromoacetylglucosamine is a true affinity label for rat muscle hexokinase type II [Connolly and Trayer (1979) Eur. J. Biochem. 93, 375–385] it inactivates the liver enzyme only very slowly. Time-dependent irreversible inactivation of glucokinase is best achieved when the bromoacetyl group is made more “mobile” by interposing at least a three-atom spacer molecule between it and the sugar ring. The substrate-unrelated but chemically similar reagents, N-bromoacetylgalactosamine and bromoacetic acid, do not inhibit glucokinase and only cause slight non-specific inactivation. The kinetics of inactivation of glucokinase by N-(N-bromoacetyl)-6-aminohexanoylglucosamine are in accord with the reversible formation of an enzyme-inhibitor complex prior to modification, indicating that the reagent is active site directed. Both glucose and N-acetylglucosamine protect competitively against inactivation. Use of 14C-labelled reagent showed that 1 mol reagent/mol protein caused complete activity loss, although an additional 1 mol/mol protein reacted without any effect on activity. The inactivation rate is relatively insensitive to pH variation over the range 6.5–9. Thus it would seem that the modified residue is not a cysteine unless it is unusually perturbed. This behaviour contrasts with that of yeast hexokinase, bovine brain hexokinase type I and rat muscle hexokinase type II with similar affinity reagents where a thiol is modified with complete activity loss.

Liver

enzymology

53950462

Personalized pathology maps to quantify diffuse and focal brain damage

Background and objectives Quantitative MRI (qMRI) permits the quantification of brain changes compatible with inflammation, degeneration and repair in multiple sclerosis (MS) patients. In this study, we propose a new method to provide personalized maps of tissue alterations and longitudinal brain changes based on different qMRI metrics, which provide complementary information about brain pathology. Methods We performed baseline and two-years follow-up on (i) 13 relapsing-remitting MS patients and (ii) four healthy controls. A group consisting of up to 65 healthy controls was used to compute the reference distribution of qMRI metrics in healthy tissue. All subjects underwent 3T MRI examinations including T1, T2, T2* relaxation and Magnetization Transfer Ratio (MTR) imaging. We used a recent partial volume estimation algorithm to estimate the concentration of different brain tissue types on T1 maps; then, we computed a deviation map (z-score map) for each contrast at both time-points. Finally, we subtracted those deviation maps only for voxels showing a significant difference with healthy tissue in one of the time points, to obtain a difference map for each subject. Results and conclusion Control subjects did not show any significant z-score deviations or longitudinal z-score changes. On the other hand, MS patients showed brain regions with cross-sectional and longitudinal concomitant increase in T1, T2, T2* z-scores and decrease of MTR z-scores, suggesting brain tissue degeneration/loss. In the lesion periphery, we observed areas with cross-sectional and longitudinal decreased T1/T2 and slight decrease in T2* most likely related to iron accumulation. Moreover, we measured longitudinal decrease in T1, T2 - and to a lesser extent in T2* - as well as a concomitant increase in MTR, suggesting remyelination/repair. In summary, we have developed a method that provides whole-brain personalized maps of cross-sectional and longitudinal changes in MS patients, which are computed in patient space. These maps may open new perspectives to complement and support radiological evaluation of brain damage for a given patient.

Brain

pathology

11752190

Merkel cell carcinoma with pagetoid spread.

A case of Merkel cell carcinoma showing epidermotropism is presented. The neoplastic cells displayed dotlike immunoreactivity for cytokeratins and strong immunoreactivity for neuron-specific enolase. Although no neuroendocrine granules were found, characteristic paranuclear fibrous bodies were present.

Skin Neoplasms

pathology

41701481

Steroid therapy during acute myocardial infarction. A cause of delayed healing and of ventricular aneurysm.

Abstract Clinical and necropsy observations are described in a man who received large doses of corticosteroids for Dressler's syndrome which complicated acute myocardial infarction. Although the patient survived for 63 days, during 53 of which he received corticosteroids, the infarct histologically appeared to be only 10 to 14 days old. Thus, the healing of the infarct was clearly delayed. Experimental studies in dogs were cited in which healing of myocardial infarction was delayed by corticosteroid therapy. In our patient a large left ventricular aneurysm also developed. Study of previous reports of human subjects receiving corticosteroids during acute myocardial infarction disclosed that aneurysmal formation was also a common complication of corticosteroid therapy for the postmyocardial infarction syndrome. It is concluded that use of glucocorticosteroids for any reason during acute myocardial infarction may be hazardous, and that their use in patients with the postmyocardial infarction syndrome, a benign and self-limited condition, should be avoided.

Myocardial Infarction

complications

39693408

The role of starvation, hypoglycemia, and adrenergic blockade on growth hormone secretion in obesity

The effects of starvation and refeeding on the circulating levels of human growth hormone (HGH) of seven obese subjects were studied with and without alpha and beta adrenergic blockade during an insulin tolerance test (ITT). The tests were performed during baseline, total fast, and refeeding periods. Autonomic blockade during starvation was not performed. The degrees of hypoglycemia produced during the mean baseline ITT before and after blockade and in the fasting period were comparable and associated with HGH levels of similar response. During refeeding, mean fasting glucose levels before and after blockade were higher than in control and fasting periods. The insulin‐induced hypoglycemia effect was comparable in percentage decrease, although absolute levels of hypoglycemia were less. There was correspondingly less response of HGH to this stimulus. This indicates that HGH secretion is normal in obesity provided sufficient hypoglycemia is produced a not apparently affected by circulating catecholamine levels.

Obesity

physiopathology

11286508

[Local excision of T1b anal canal cancer - a case report].

We performed transanal local excision of anal canal cancer in a 51-year-old man. The tumor was detected as an Isp polyp(7 mm)on the dentate line, by colonofiberscopic examination. Pathological findings indicated adenocarcinoma(T1b). The patient desired preservation of anal function, and hence refused abodominoperineal rectal transection with lymph node dissection. We obtained informed consent for recurrence, and observed the patient rigorously. No recurrence or metastasis has been detected 3 years and 3 months after tumor excision. We propose that transanal local excision might be a treatment option for early stage cancer of the anal canal.

Adenocarcinoma

surgery

3328259

Screening for Viral Hepatitis and Hepatocellular Cancer.

Accurate tests for at-risk populations are available for hepatitis B virus, hepatitis C virus (HCV), and hepatocellular carcinoma (HCC). Effective treatments for all three diseases exist if diagnosed early. New antivirals are making a significant impact on HCV. Liver transplant is curative for early HCC and is prioritized by the United Network for Organ Sharing in the United States. Screening and surveillance for deadly disease only makes sense if there are identifiable populations at risk for the condition, there are sensitive and specific low-cost tests available for the condition, and there are effective treatments for the condition.

Liver Neoplasms

diagnosis

12061807

Binocular vision and eye movement disorders in older adults.

PURPOSE To determine the prevalence of binocular vision (BV) and eye movement disorders in a clinic population of older adults. METHODS Retrospective clinic data were abstracted from files of 500 older patients seen at the University of Waterloo Optometry Clinic over a 1-year period. Stratified sampling gave equal numbers of patients in the 60 to 69, 70 to 79, and 80+ age groups. Data included age, general and ocular history and symptoms, use of antidepressants, a habit of smoking, refraction, visual acuity, BV and eye movement status for the most recent full oculo-visual assessment, and an assessment 10 years prior. The prevalence of any BV or eye movement abnormal test (AT) result, defined as a test result outside the normal range, was determined. This included strabismus (any) or phoria; incomitancy; poor pursuits; and remote near point of convergence (NPC). The prevalence of significant BV disorders (diagnostic entities, i.e., a clinical condition that may need treatment and may have functional implications) was also determined. RESULTS The prevalence of any BV or eye movement at was 41%, 44%, and 51% in the 60 to 69, 70 to 79, and 80+ age groups, respectively. These figures were lower for 10 years earlier: 31%, 36%, and 40% for ages 50 to 59, 60 to 69, and 70+, respectively. The prevalence of any BV or eye movement disorder was 27%, 30%, and 38% for the three age groups and 17%, 19%, and 24% for 10 years prior. Age and use of antidepressants most commonly predicted BV or eye movement AT or disorder. CONCLUSIONS BV disorders are common among older adults.

Aging

physiology

89210546

Human chromosome functional characteristics and aging

The MUTATION level (chromosome aberrations covering telomere regions), MODIFICATIONS of CHROMOSOME STRUCTURE (level of condensed chromatin identified by the methods of electron microscopy and differential scanning microcalorimetry; level of C-banding constitutive heterochromatin; transcriptional activity of DNA-dependent RNA polymerase; Ag-positive NORs and associations of acrocentric chromosomes) and REPARATION (intensity of unscheduled DNA synthesis and the frequency of sister chromatid exchanges) have been studied in lymphocyte cultures from individuals at the age of 70-114 to reveal the chromosome functional organization at late stages of ontogenesis and to find explanations of some senile pathologies. The analysis of obtained results showed: 1) chromosome progressive heterochromatinization (condensation of eu- and heterochromatin regions) occurs at aging; 2) decrease of repair processes and increase in frequency of chromosome aberrations in aging are secondary to the progressive heterochromatinization. Chromosome heterochromatinization is a key factor of aging; 3) chromosome heterochromatinization may be the reason for some senile pathologies; 4) chromosome heterochromatinization is an area where one should seek the ways for prolonging the lifespan.

Aging

physiology

26721199

"Cervia II Working Group Report 2006": guidelines on diagnosis and treatment of Helicobacter pylori infection in Italy.

Proper management of Helicobacter pylori infection in clinical practice--when supported by evidence-based data--is expected to produce substantial cost-efficacy advantages. This consideration has prompted the Cervia Working Group to organise a meeting of experts to update the National Guidelines on the diagnosis and treatment of H. pylori infection in Italy. Recommendations in the new European Guidelines were considered in the National setting, here in the light of factors such as the incidence of gastric cancer and gastric lymphoma, the accessibility to different diagnostic tools, the prevalence of bacterial resistance against antibiotics, and the availability of different drugs. The main revisions in respect to the previous guidelines include H. pylori eradication in non-ulcer dyspepsia patients and in non-steroidal, anti-inflammatory drug users, as well as in patients with idiopathic thrombocytopenic purpura and iron deficiency anaemia. The stool antigen test is now accepted as a valid test for confirmation of H. pylori eradication following therapy. New therapeutic approaches have been recommended for both first- (sequential therapy) and second-line (levofloxacin-based) treatment in our country.

Anti-Bacterial Agents

therapeutic use

12628634

Serum testosterone levels in South African men and the onset of androgen decline in ageing males.

Malignant melanoma of the vermilion of the lip is a rare entity, and because of the common occurrence of other benign pigmented lesions, it is easily overlooked. Early diagnosis is of the utmost importance, in the first instance to minimise the risk of haematogenous, lymphatic, perineural and trans- (salivary) ductal spread. The second reason for early diagnosis is that surgery is the only effective form of treatment. A number of important clinical lessons were learned from this cohort study of malignant melanoma of the vermillion of the lip. Two observations are of note - first, the absence of palpable regional lymph nodes does not exclude the presence of a malignant melanoma, yet all patients presenting with palpable nodes were suffering from a preterminal disease. Secondly, apart from 1 case (our case 2), melanoma of the lip seems to occur on the lower lip only. There are no clear guidelines regarding the necessary extent of extirpation for malignant melanoma of the vermilion of the lip, but we propose that clear margins of less than 10 mm are probably inadequate and margins of more than 20 mm are unnecessary. Concern about a resection resulting in a 20 mm clear margin all round is seldom justified as excellent methods of reconstruction achieving acceptable mobile, adequately sensate lips are available.

Aging

physiology

19937168

Safety and efficacy of antibiotics among acutely decompensated cirrhosis patients

Infection is a leading precipitant of acute‐on‐chronic liver failure. This study aims to determine the safety and efficacy of antibiotics within acute‐on‐chronic liver failure.

Anti-Bacterial Agents

therapeutic use

41454745

Clinical management of carcinoma of prostate, associated with bilateral ureteral obstruction.

A review of 34 cases of bilateral ureteral obstruction secondary to carcinoma of the prostate indicates that aggressive treatment in selected cases can increase survival without an associated increase in morbidity. In our series various modalities of treatment were used in 25 patients and the remaining 9 patients received no treatment. Bilateral ureteral obstruction in cases of carcinoma of the prostate should not uniformly imply a terminal event or hopeless prognosis.

Prostatic Neoplasms

therapy

198134313

Opioids Affect the Fetal Brain: Reframing the Detoxification Debate.

Medication-Assisted Treatment is recommended for individuals with an opioid use disorder including pregnant women. Medication-Assisted Treatment during pregnancy provides benefits to the mother and fetus including better pregnancy outcomes, reduced illicit drug use and improved prenatal care. An alternative approach, medically supervised withdrawal (detoxification), has, in recent reports, demonstrated a low risk of fetal death, low rates of relapse and Neonatal Abstinence Syndrome. The rates of relapse and Neonatal Abstinence Syndrome are questioned by many who view medically supervised withdrawal as unacceptable based on the concern for the potential adverse consequences of relapse to mother and baby. The impact of opioids on the fetal brain have not been integrated into this debate. Studies in animals and human brain tissues demonstrate opioid receptors in neurons, astroglia and oligodendrocytes. Age specific normative data from infants, children and adults have facilitated investigation of the impact of opioids on the human brain in-vivo. Collectively, these studies in animals, human neural tissue, adult brains, the brains of children and newborns demonstrate that opioids adversely affect the human brain, primarily the developing oligodendrocyte and the processes of myelinization (white matter microstructure), connectivity between parts of the brain and the size of multiple brain regions including the basal ganglia, thalamus and cerebellar white matter. These in vivo studies across the human lifespan suggest vulnerability of specific fronto-temporal-limbic and frontal-subcortical (basal ganglia and cerebellum) pathways which are also likely vulnerable in the human fetal brain. The long- term impact of these reproducible changes in the fetal brain in vivo is unclear but the possibility of lasting injury has been suggested. In light of the recent data on medically supervised withdrawal and the emerging evidence suggesting adverse effects of opioids on the developing fetal brain, a new paradigm of care is needed that includes the preferred option of medication-assisted treatment but also the option of medically supervised opioid withdrawal for a select group of women. Both these treatment options should offer mental health and social services support throughout pregnancy. More research on both opioid exposure on the developing human brain and the impact of medically supervised withdrawal is required to identify appropriate candidates, optimal dose reduction regimens and gestational age timing for initiating medically supervised withdrawal.

Brain

diagnostic imaging

21927384

Residual heat of laparoscopic energy devices: how long must the surgeon wait to touch additional tissue?

BackgroundEnergy devices are essential laparoscopic tools. Residual heat is defined as the increased instrument temperature after energy activation is completed. This study aimed to determine the length of time a surgeon needs to wait before touching other tissue using four common laparoscopic energy sources.MethodsThermal imaging quantified instrument and tissue temperature ex vivo using monopolar coagulation, argon beam coagulation, ultrasonic dissection, and bipolar tissue fusion devices. To simulate realistic operative usage, each instrument was activated for 5 s four consecutive times with 5 s pauses between fires. Thermal conductivity to bovine liver tissue was measured 2.5, 5, 10, and 20 s after final activation.ResultsThe maximum increase in instrument tip temperature was 172 ± 63°C for the ultrasonic dissection, 81 ± 18°C for the monopolar coagulation, 46 ± 19°C for the bipolar tissue fusion, and 1 ± 1°C for the argon beam coagulation (P < 0.05 for all comparisons). Touching the instrument tip to tissue at four intervals after the final activation (2.5, 5, 10, and 20 s) found that ultrasonic energy raised the tissue temperature higher (maximum change, 58°C) than the other three energy devices at all four time points (P < 0.05).ConclusionsUltrasonic energy instruments have greater residual heat than monopolar electrosurgery, bipolar tissue fusion, and argon beam. The ultrasonic energy instrument tips heated tissue more than 20°C from baseline even 20 s after activation; whereas all the other energy sources raised the tissue temperature less than 20°C by 5 s. These practical findings may alter a surgeon’s usage of these common energy devices.

Liver

surgery

16223710

Antiinflammatory effects of salmeterol after inhalation of lipopolysaccharide by healthy volunteers.

RATIONALE Salmeterol is a beta2-adrenoreceptor agonist used in the treatment of obstructive pulmonary disease. Salmeterol inhibits inflammatory responses by neutrophils and mononuclear cells in vitro and in mouse models of lung inflammation in vivo. OBJECTIVE To determine the effect of salmeterol on LPS-induced lung inflammation in humans. METHODS Thirty-two healthy subjects were enrolled in a single-blinded, placebo-controlled study. Subjects inhaled 100 microg salmeterol or placebo (t=-0.5 h) followed by 100 microg LPS or normal saline (t=0 h; n=8/group). Measurements were performed in bronchoalveolar lavage fluid and purified alveolar macrophages obtained 6 h post-challenge. MEASUREMENTS AND MAIN RESULTS Inhalation of LPS was associated with neutrophil influx, neutrophil degranulation (myeloperoxidase, bactericidal/permeability-increasing protein and elastase), release of cytokines (tumor necrosis factor alpha and interleukin 6) and chemokines (interleukin 8, epithelial cell-derived neutrophil attractant 78, macrophage inflammatory proteins 1alpha and 1beta), activation of alveolar macrophages (upregulation of HLA-DR and CD71; enhanced expression of mRNAs for 13 different mediators of inflammation), and protein leakage (all p<0.05 vs. placebo/saline). Pretreatment with salmeterol inhibited LPS-induced neutrophil influx, neutrophil degranulation (myeloperoxidase), tumor necrosis factor alpha release, and HLA-DR expression (all p<0.05 vs. placebo/LPS), while not significantly influencing other responses. CONCLUSION Salmeterol exerts antiinflammatory effects in the pulmonary compartment of humans exposed to LPS.

Lung

drug effects

20423393

Is 1,4-dioxane a genotoxic carcinogen?

Female Sprague-Dawley rats were given 0, 168, 840, 2550 or 4200 mg/kg of 1,4-dioxane 21 and 4 h before sacrifice. Hepatic DNA damage (by the alkaline elution technique), ornithine decarboxylase activity (ODC), reduced glutathione content, cytochrome P-450 content and serum alanine aminotransferase activity (ALT) were determined. Treatment with 1,4-dioxane increased hepatic DNA damage and cytochrome P-450 content at doses of 2550 and 4200 mg/kg. Large increases in the activity of hepatic ODC were observed at 840, 2550 and 4200 mg/kg of 1,4-dioxane. Thus the data suggest that 1,4-dioxane is a weak genotoxic carcinogen in addition to being a strong promoter of carcinogenesis (a non-genotoxic carcinogen).

DNA

drug effects

40019979

Neurotoxic effects of exogenous recombinant tissue-type plasminogen activator on the normal rat brain.

Thrombolytic therapy with intravenous and intra-arterial recombinant tissue-type plasminogen activator (rtPA) has been established for the treatment of acute ischemic stroke. However, tPA has also been suggested to have neurotoxic effects. The purpose of this study was to examine direct neurotoxicity of rtPA in vivo. The animals (Wistar rats) were divided to the following three groups: low-dose (15 micromol/L) rtPA group (n = 6); high-dose (30 micromol/L) rtPA group (n = 6); and control (physiological saline) group (n = 6). The rtPA solution was perfused into the cortex via a microdialysis probe. The volume of the lesion was quantified histologically by image analysis of the lesions. Blood-brain barrier (BBB) disruption was evaluated by intravenous injection of Evans blue, and injury to the basal lamina was evaluated by immunohistochemistry using an anti-laminin antibody. In the rtPA-perfused animals, a pale lesion was produced around the probe, and microscopically, neurons showed necrotic changes. The volume of the lesions increased significantly as the concentration of perfused rtPA was increased. Marked extravasation of Evans blue was observed, and laminin immunoreactivity of blood vessels in the rtPA-induced lesions was lost. These results suggest that rtPA promotes acute direct neurotoxicity and participates in disruption of the microvascular basal lamina to cause BBB disruption, thereby increasing edema formation.

Brain

pathology

22132005

Dynamic use of tumor markers, rationale-clinical applications and pitfalls.

The dynamic evaluation of tumor markers is a promising area of investigation which is expected to provide clinical information when serial samples are available from the same patient. This is feasible in the post-operatory evaluation, during the follow-up after the treatment for to the primary tumor and in the monitoring of the treatment for metastatic disease. Variations among serial samples may be assessed using both empirical and mathematical approaches. Empirical approaches rely on overcoming a given percentage usually chosen on the base of arbitrary decisions. Mathematical approaches include the actual half-life, the doubling time, a dose/time regression analysis and the calculation of the critical difference. The two former are currently used in clinical practice whereas the two latter are still matter of investigation. As concerns the assessment of the radicality of the surgery for the primary tumor, the serum markers are used in germ cell tumors and in prostate cancer. The half-life of the markers is the decision criteria used in germ cell cancers, while in prostate cancer PSA is expected to be undetectable more than 30 days after the radical prostatectomy. Tumor markers are currently used during the follow-up of several malignancies after the treatment for primary tumor. Although several samples are available, decision criteria are still based on positive/negative cut-off values in several instances. Promising dynamic approaches are under investigation and are expected to lead to earlier and probably more accurate information concerning the disease progression. A critical point still under debate is the actual impact of tumor markers on patients' survival in malignancies incurable when metastatic, such as colorectal cancer and breast cancer. This matter urgently demands perspective clinical studies. Finally, the dynamic use of tumor markers is now commonly applied in the monitoring of the therapy for metastatic malignancies. In this clinical setting mathematical criteria are used for ovarian and and germ cell tumors with promising results. Nevertheless, the use of empirical criteria, namely the percentage of variation between two consecutive samples, is successfully used for the monitoring of the therapy of metastatic breast cancer. In conclusion, when several samples are available from an individual patient they may be evaluated according to dynamic criteria instead of referring to a conventional positive/negative cut-off point. Although mathematical decision criteria are expected to provide more reliable data, empirical approaches are used as well and provide useful information in decision making.

Neoplasms

diagnosis

29886869

Carcinoembryonic antigen and interferon as tumor markers in breast cancer

A total of 239 determinations of CEA plasma levels were performed for 83 breast cancer patients during chemotherapy or follow‐up. In addition, 137 plasma samples were assayed for interferon levels. Patient clinical status was carefully scored according to objective criteria and recorded at each evaluation. Liver function tests (LFT) were performed to establish a full clinical picture at each visit. The results obtained proved a 73 to 83% positivity rate when the results of the 4 tests were compared. The importance of routine CEA assays and careful clinical evaluation and LFT are stressed. An analysis of interferon levels defined 4 distinct groups that differed by the amount of interferon present and also by clinical status and CEA levels. The results are discussed in terms of tumor volume‐dependent interferon production.

Breast Neoplasms

metabolism

36797157

Analysis of vocal and swallowing functions after horizontal glottectomy.

We conducted a cross-sectional study to assess vocal and swallowing functions after horizontal glottectomy. Our study population was made up of 22 men aged 45 to 72 years (mean: 58.3) who underwent horizontal glottectomy and completed at least 1 year of follow-up. To compare postoperative results, 20 similarly aged men were included as a control group; all glottectomy patients and all controls were smokers. We used three methods-acoustic and aerodynamic voice analyses, the GRBAS (grade, roughness, breathiness, asthenicity, and strain) scale, and the voice handicap index-30 (VHI-30)-to assess vocal function objectively, perceptually, and subjectively, respectively. We also assessed swallowing function objectively by fiberoptic endoscopic evaluation of swallowing (FEES) and subjectively with the M.D. Anderson dysphagia inventory (MDADI). The 22 patients were also subcategorized into three groups according to the extent of their arytenoid cartilage resection, and their outcomes were compared. Acoustic and aerodynamic analyses showed that the mean maximum phonation time was significantly shorter and the fundamental frequency was significantly lower in the glottectomy group than in the controls (p = 0.001 for both), and that the mean jitter and shimmer values and the mean harmonics-to-noise ratio were all significantly higher (p = 0.001 for all); there were no significant differences among the three arytenoid subgroups. Self-assessments revealed that there were no statistically significant differences among the three subgroups in GRBAS scale scores except for the breathiness score (p = 0.045), which was lower in the arytenoid preservation subgroup than in the total resection subgroup; there were no statistically significant differences among the three subgroups in VHI-30 scores. Finally, swallow testing found no statistically significant differences in FEES scores or MDADI scores. We conclude that horizontal glottectomy caused a deterioration in vocal function, but swallowing function was satisfactory.

Postoperative Complications

physiopathology

21998002

[Rehmanniae Radix and Rehmanniae Radix Praeparata Ameliorates Renal Interstitial Fibrosis Induced by Unilateral Ureteral Occlusion in Rats and Their Mechanism].

OBJECTIVE To study the effects of Rehmanniae Radix and Rehmanniae Radix Praeparata on renal interstitial fibrosis (RIF) of obstructed kidneys in a unilateral ureteral obstruction (UUO) rat model and the mechanism. METHODS 20 rats were randomly divided into four groups : sham operated group, UUO group, Rehmanniae Radix decoction group and Rehmanniae Radix Praeparata decoction group. The sham operated group and the UUO group were orally administered normal saline, the drug groups were orally administered 1.6 g/(kg x d) of Rehmanniae Radix decoction and Rehmanniae Radix Praeparata decoction for 14 days, respectively. Then the serum of rats were collected for measurements of Scr and BUN contents. Histological changes of kidneys were observed by HE and Masson staining. The expression of transforming growth factor-β1, (TGF-β1), α-smooth muscle actin (α-SMA) and type I collagen (Collagen-I) were detected by Western blot method. RESULTS Compared with model group, the contents of Scr and BUN in rats serum of drug groups were significantly decreased (P < 0.05), the sclerosis of glomerulus was ameliorated, the degree of saccular dilatation and the damage of tubules were alleviated, collagen distribution and interstitial fibrosis was obviously improved,while the expressions of TGF-β1, α-SMA and Collagen-I were decreased. Compared with Rehmanniae Radix Praeparata decoction group,the contents of Scr and BUN in rats serum of Rehmanniae Radix decoction group were lower, the decrease of collagen distribution and interstitial fibrosis were more obviously, while the expression of α-SMA was significantly decreased (P < 0.05). CONCLUSION The effect of Rehmanniae Radix is more powerful than that of Rehmanniae Radix Praeparata on attenuating interstitial fibrosis,which may relative to downregulating the expressions of TGF-β1, α-SMA and Collagen-I.

Kidney

pathology

21371154

Description of artefacts in the PowerPlex Y23(®) system associated with excessive quantities of background female DNA.

Male on female sexual assault cases that involve azoospermic individuals, those where the male has penetrated but failed to ejaculate, those where there has been an extended interval between the sexual assault and sample collection or where there has been only digital penetration are often difficult to investigate by employing traditional autosomal STR testing. Such cases often involve minimal amounts of male DNA either being deposited initially or remaining after the passage of time. These cases are often further complicated by the presence of large amounts of female DNA compared to the relatively small amounts of male DNA on the intimate samples taken. Y-STR kits provide a solution that allows targeting of male DNA in a mixed male/female sample. However, large quantities of excess female DNA have the potential to generate non-specific artefact peaks. Here we characterise a number of previously reported artefacts observed in the PowerPlex(®) Y23 system. We demonstrate that some of these artefacts can impact on profile interpretation and that they are highly dependent on the levels of female DNA present. These artefacts have been characterised to assist practitioners with the interpretation of such samples.

DNA

analysis

23032266

Transbronchial needle aspiration in the diagnosis of bronchogenic carcinoma.

Transbronchial needle aspiration (TBNA) via a fiberoptic bronchoscope has been used for diagnosis of lung cancer by Wang since 1981. The technique uses a fiberoptic bronchoscope with a flexible needle that can penetrate the wall of the trachea and major bronchi. It is still underutilized and markedly depends on the physician's skill. We present our experience of TBNA for diagnosis of bronchogenic carcinoma. TBNA was performed on 47 consecutive patients with suspected lung cancer at the time of diagnosis bronchoscopy. Thirty six patients were diagnosed with bronchogenic carcinoma. TBNA demonstrated bronchogenic carcinoma in 61.1 per cent of the cases (22 of 36) and TBNA alone confirmed a malignant diagnosis in 33.3 per cent (12 of 36). The overall diagnostic yield of bronchoscope utilizing the conventional techniques of bronchial washing, brushings and biopsy was 50 per cent. With the addition of TBNA, bronchoscopy was diagnostic in 83.3 per cent of the patients. There were no serious complications. We concluded that TBNA is a safe technique that can significantly increase the diagnostic yield of conventional fiberoptic bronchoscopy in the diagnosis of bronchogenic carcinoma.

Lung Neoplasms

pathology

9488238

Influence of the CCR-5/MIP-1 α axis in the pathogenesis of Rocio virus encephalitis in a mouse model.

Rocio virus (ROCV) caused an outbreak of human encephalitis during the 1970s in Brazil and its immunopathogenesis remains poorly understood. CC-chemokine receptor 5 (CCR5) is a chemokine receptor that binds to macrophage inflammatory protein (MIP-1 α). Both molecules are associated with inflammatory cells migration during infections. In this study, we demonstrated the importance of the CCR5 and MIP-1 α, in the outcome of viral encephalitis of ROCV-infected mice. CCR5 and MIP-1 α knockout mice survived longer than wild-type (WT) ROCV-infected animals. In addition, knockout mice had reduced inflammation in the brain. Assessment of brain viral load showed mice virus detection five days post-infection in wild-type and CCR5-/- mice, while MIP-1 α-/- mice had lower viral loads seven days post-infection. Knockout mice required a higher lethal dose than wild-type mice as well. The CCR5/MIP-1 α axis may contribute to migration of infected cells to the brain and consequently affect the pathogenesis during ROCV infection.

Brain

pathology

38077332

Gap Junction-Mediated Bidirectional Signaling between Human Fetal Hippocampal Neurons and Astrocytes

Gap junctions are clusters of intercellular channels that connect the interiors of coupled cells. In the brain, gap junctions function as electrotonic synapses between neurons and as pathways for the exchange of metabolites and second-messenger molecules between glial cells. Astrocytes, the most abundant glial cell type coupled by gap junctions, are intimately involved in the active control of neuronal activity including synaptic transmission and plasticity. Previous studies have suggested that astrocytic-neuronal signaling may involve gap junction-mediated intercellular connections; this issue remains unresolved. In this study, we demonstrate that second-trimester human fetal hippocampal neurons and astrocytes in culture are coupled by gap junctions bidirectionally; we show that human fetal neurons and astrocytes express both the same and different connexin subtypes. The formation of functional homotypic and heterotypic gap junction channels between neurons and astrocytes may add versatility to the signaling between these cell types during human hippocampal ontogeny; disruption of such signaling may contribute to CNS dysfunction during pregnancy.

Neurons

cytology

8061242

[Intraoperative and early postoperative intraperitoneal chemotherapy--adjuvant treatment for locally advanced digestive system cancer].

UNLABELLED Surgical treatment for locally advanced digestive cancers (invasion beyond the serosa, adjacent structures penetration and perforated tumors) is followed by a high rate of peritoneal recurrence and distant metastasis. Simultaneous intraperitoneal chemotherapy with surgical resection, which is continued over the early postoperative period act on the tumor cells which can be mobilized during the surgical dissection. This adjuvant treatment could lead to better control of local recurrence. Moreover, high levels of the agents are reached in the portal circulation which could be profitable for preventing hepatic metastasis. The main drawback of the method is represented by the impaired immunologic activity of the peritoneum, which can cause, at least theoretically, detrimental complications. OBJECTIVE The efficiency of the intraoperative and early postoperative intraperitoneal chemotherapy is the subject of a prospective randomized study, started 8 months ago in our department. METHOD Patients with locally advanced (penetration of the tumor beyond serosal layer, without liver metastasis) are randomized for adjuvant intraperitoneal chemotherapy or standard treatment. Intraoperative chemotherapy is commenced after surgical resection but before accomplishing any anastomosis. We use 50 mg of cisplatinum for washing the peritoneal cavity and continue to instill 20 mg/m2 of cisplatinum intraperitoneally in the first four days after surgery. (8 patients were selected to be treated according to this protocol). CONCLUSION Immediate postoperative outcome does not seem to be influenced by this treatment. The disease free interval and the overall survival rates can not be assessed at this moment of the study.

Antineoplastic Agents

administration & dosage

24285996

The twin-arginine translocation pathway is a major route of protein export in Streptomyces coelicolor

The twin-arginine translocation (Tat) pathway is a protein transport system for the export of folded proteins. Substrate proteins are targeted to the Tat translocase by N-terminal signal peptides harboring a distinctive R-R-x-Φ-Φ “twin-arginine” amino acid motif. Using a combination of proteomic techniques, the protein contents from the cell wall of the model Gram-positive bacterium Streptomyces coelicolor were identified and compared with that of mutant strains defective in Tat transport. The proteomic experiments pointed to 43 potentially Tat-dependent extracellular proteins. Of these, 25 were verified as bearing bona fide Tat-targeting signal peptides after independent screening with a facile, rapid, and sensitive reporter assay. The identified Tat substrates, among others, include polymer-degrading enzymes, phosphatases, and binding proteins as well as enzymes involved in secondary metabolism. Moreover, in addition to predicted extracellular substrates, putative lipoproteins were shown to be Tat-dependent. This work provides strong experimental evidence that the Tat system is used as a major general export pathway in Streptomyces.

Bacterial Proteins

metabolism

11538722

X-ray crystallography and the elucidation of the structure of DNA.

OBJECTIVE Since their discovery by Roentgen in 1895, x-rays have contributed to some of the most important advances in science. X-ray crystallography is an imaging technique that uses x-ray diffraction to evaluate the molecular structure of a crystalline solid. This article discusses the critical role played by x-ray crystallography in the elucidation of the structure of DNA. CONCLUSION The story of DNA includes insights on molecular structure provided by x-rays and also lessons on scientific collaboration and innovation that can be applied to radiology today.

DNA

chemistry

10812087

The burden of HIV-related illness on outpatient health services in KwaZulu-Natal, South Africa

Abstract Health services in sub-Saharan Africa will be faced with increasing numbers of AIDS patients for many years to come. Where there is good availability of drugs and other resources, the costs of treating HIV/AIDS is likely to be higher than those of treating other types of illness. This will put services under strain and potentially jeopardise health system reform, depending on the vulnerability of the system. Whereas previous research has focussed on inpatients, this paper looks at the impact of HIV/AIDS on outpatient services in a district of South Africa. Through facility visits at various levels of care, data concerning HIV status and the costs of care was collected for all patients presenting over a set period of time. The proportion of patients presenting for HIV-related care ranged from 20.2 to 24.5%. The average costs of treating HIV-positive patients were significantly higher than those for non HIV patients at hospitals, with clinics not experiencing this difference due to the limited service provided. District hospitals spent the greatest proportion of direct patient care resources on treating HIV-related illness. In terms of outpatient care, this data suggests that district hospitals may require the most support in dealing with a rising number of AIDS patients.

HIV Infections

economics

12514247

Disruption of phosphatidylserine translocation to the mitochondria in baby hamster kidney cells.

Phosphatidylserine synthase is found predominantly in the microsomal fraction, and phosphatidylserine decarboxylase is found predominantly in the mitochondrial fraction of baby hamster kidney (BHK-21) cells. This segregation of enzymes of phosphatidylserine metabolism allows serine metabolism to phosphatidylserine and phosphatidylethanolamine to be used as an indicator of the intracellular movement of phosphatidylserine. After BHK-21 cells were pulse-labeled with [3H]serine, phosphatidylserine was efficiently labeled, and subsequently 40-50% of this radiolabeled lipid turned over to form phosphatidylethanolamine during a 7.5-h chase. Treatment of cells with NaN3 plus NaF or cycloheximide at the end of the pulse labeling period markedly inhibited the rate and extent of phosphatidylserine turnover during the chase period. The inhibition of phosphatidylserine turnover could not be attributed to inhibition of either phosphatidylserine decarboxylase or phosphatidylserine exchange protein activity. Subcellular fractionation of the BHK-21 cells demonstrated that cells poisoned with NaN3 plus NaF accumulated phosphatidylserine in the microsomal fraction relative to unpoisoned cells. The results indicate that metabolic energy is required for the transport of phosphatidylserine to the mitochondria.

Kidney

metabolism

4935942

Increased Dependence of Action Selection on Recent Motor History in Parkinson's Disease

It is well known that the basal ganglia are involved in switching between movement sequences. Here we test the hypothesis that this contribution is an instance of a more general role of the basal ganglia in selecting actions that deviate from the context defined by the recent motor history, even when there is no sequential structure to learn or implement. We investigated the effect of striatal dopamine depletion [in Parkinson's disease (PD)] on the ability to switch between independent action plans. PD patients with markedly lateralized signs performed a hand laterality judgment task that involved action selection of their most and least affected hand. Trials where patients selected the same (repeat) or the alternative (switch) hand as in a previous trial were compared, and this was done separately for the most and least affected hand. Behaviorally, PD patients showed switch-costs that were specific to the most affected hand and that increased with disease severity. Functional magnetic resonance imaging (fMRI) showed that this behavioral effect was related to the state of the frontostriatal system: as disease severity increased, contributions of the basal ganglia to the selection process and their effective connectivity with the medial frontal cortex (MFC) decreased, whereas involvement of the MFC increased. We conclude that the basal ganglia are important for rapidly switching toward novel motor plans even when there is no sequential structure to learn or implement. The enhanced MFC activity may result either from reduced focusing abilities of the basal ganglia or from compensatory processes.

Brain

physiopathology

29195430

Comparison of dose distribution by means of bolus versus water bath phantom techniques in treatment of cutaneous sarcoma of an extremity.

Cutaneous involvement by Kaposi's sarcoma (KS) is frequently diffuse, requiring large field irradiation. Selective tissue compensation techniques, accomplished with either a 1.5 cm bolus cast or water bath phantom, are compared. Dosimetric determinations were performed using 6 MVX with bone heterogeneity corrections. Application of 1.5 cm bolus effectively eliminated dose buildup and provided tissue compensation equivalent to water bath phantom technique. Treatment of other cutaneous malignancies, such as angiosarcoma, requiring higher total doses, should be accompanied by dosimetric evaluation, because cutaneous and midline dose inhomogeneity may result in a significant total dose differential over the target volume. Application of 1.5 cm bolus improved accuracy in treatment positioning, eliminated concerns regarding infection control in AIDS-related KS, and provided dose homogeneity comparable to the more standard water bath phantom technique.

Skin Neoplasms

radiotherapy

6505081

Predictors of Dropout by Female Obese Patients Treated with a Group Cognitive Behavioral Therapy to Promote Weight Loss

Objective: To investigate predictors of dropout from a group cognitive behavioral therapy (CBT) intervention for overweight or obese women. Methods: 119 overweight and obese Japanese women aged 25-65 years who attended an outpatient weight loss intervention were followed throughout the 7-month weight loss phase. Somatic characteristics, socioeconomic status, obesity-related diseases, diet and exercise habits, and psychological variables (depression, anxiety, self-esteem, alexithymia, parenting style, perfectionism, and eating attitude) were assessed at baseline. Significant variables, extracted by univariate statistical analysis, were then used as independent variables in a stepwise multiple logistic regression analysis with dropout as the dependent variable. Results: 90 participants completed the weight loss phase, giving a dropout rate of 24.4%. The multiple logistic regression analysis demonstrated that compared to completers the dropouts had significantly stronger body shape concern, tended to not have jobs, perceived their mothers to be less caring, and were more disorganized in temperament. Of all these factors, the best predictor of dropout was shape concern. Conclusion: Shape concern, job condition, parenting care, and organization predicted dropout from the group CBT weight loss intervention for overweight or obese Japanese women.

Obesity

therapy

25427805

The effects of age on lens transport.

PURPOSE Age-related nuclear cataracts involve denaturation and aggregation of intracellular proteins. We have documented age-dependent changes in membrane transport in the mouse lens to see what might initiate changes in the intracellular milieu. METHODS Microelectrode-based intracellular impedance studies of intact lenses were used to determine gap junction coupling conductance, fiber and surface cell membrane conductances, effective extracellular resistivity, and intracellular voltage. Fiber cell connexin expression was detected by Western blotting. Intracellular hydrostatic pressure was measured with a microelectrode/manometer system. Concentrations of intracellular sodium and calcium were measured by intracellular injection of sodium-binding benzofuran isophthalate and Fura2, respectively. RESULTS In adult lenses, as age increased: fiber cell gap junction coupling conductance declined significantly, correlating with decreases in Cx46 and Cx50 labeling in Western blots; fiber and surface cell membrane conductances did not change systematically; effective extracellular resistivity increased monotonically; center to surface gradients for intracellular pressure, sodium, calcium, and voltage all increased, but in an interdependent manner that moderated changes. In newborn pup lenses, there were changes that did not simply fit with the above paradigm. CONCLUSIONS In newborn pup lenses, the observed changes may relate to growth factors that are not related to age-dependent changes seen in adult lenses. The major change in adult lenses was an age-dependent decrease in gap junction coupling, probably due to oxidative damage leading to degradation of connexin proteins. These changes clearly lead to compromise of intracellular homeostasis and may be a causal factor in age-related nuclear cataracts.

Aging

psychology

7577784

Advances in cancer immunotherapy.

Abstract Specific engagement of immune effector functions is a rapidly advancing field within experimental tumor therapy. A recent meeting**The 2nd International Dresden Symposium on Immunotherapy of Cancer was held at Dresden, Germany, on 12-13 June 1998. focused on the analysis of cellular and humoral immune responses against tumors and on clinical trials of antitumor vaccination and antibody therapy.

Neoplasms

therapy

46209442

Catch-bond model derived from allostery explains force-activated bacterial adhesion.

High shear enhances the adhesion of Escherichia coli bacteria binding to mannose coated surfaces via the adhesin FimH, raising the question as to whether FimH forms catch bonds that are stronger under tensile mechanical force. Here, we study the length of time that E. coli pause on mannosylated surfaces and report a double exponential decay in the duration of the pauses. This double exponential decay is unlike previous single molecule or whole cell data for other catch bonds, and indicates the existence of two distinct conformational states. We present a mathematical model, derived from the common notion of chemical allostery, which describes the lifetime of a catch bond in which mechanical force regulates the transitions between two conformational states that have different unbinding rates. The model explains these characteristics of the data: a double exponential decay, an increase in both the likelihood and lifetime of the high-binding state with shear stress, and a biphasic effect of force on detachment rates. The model parameters estimated from the data are consistent with the force-induced structural changes shown earlier in FimH. This strongly suggests that FimH forms allosteric catch bonds. The model advances our understanding of both catch bonds and the role of allostery in regulating protein activity.

Escherichia coli

metabolism

36429986

College-educated women's personality development in adulthood: perceptions and age differences.

Adulthood encompasses a large time span and includes a series of psychosocial challenges (E. H. Erikson, 1950). Five aspects of personality (identity certainty, confident power, concern with aging, generativity, and personal distress) were assessed in a cross-sectional study of college-educated women who at the time of data collection were young adults (age: M = 26 years), middle-aged adults (age: M = 46 years), or older adults (age: M = 66 years). Respondents rated each personality domain for how true it was of them at the time, and they then rated the other 2 ages either retrospectively or prospectively. Results are discussed with attention to the ways in which women's adult development may have been shaped by experiences particular to both gender and birth cohort, and to how these women fit with E. H. Erikson's theory of adult development.

Aging

psychology

85020699

Isolation and Properties of Human α-Fetoprotein from HepG2 Cell Cultures

A relatively rapid 3-step fractionation method has been developed for the isolation of human α-fetoprotein from culture fluids of HepG2 cells applicable to large volumes. The protein exists as a complex with lipids or lipoproteins but an ethanol precipitation step is effective in separating it. Yields of 50–60% can be obtained from culture fluid containing 30–40 μg/ml. A minor fraction that appears to be a proteolytic product of the AFP is present in the final product.

Liver Neoplasms

chemistry

42702651

Normal to cancer microbiome transformation and its implication in cancer diagnosis.

Microbial communities coexisting with humans are collectively known as microbiome. It influences almost every aspect of an individual's body function. Microbiome is idiosyncratic for body condition and its alteration is indicative for several abnormalities. This article discusses about recent ideas for developing microbiology based cancer indicators using alterations in microbiome. It is noteworthy that large exploratory studies are required to identify cancer indicator microorganisms from complex and diverse microbiome constituents. This complexity also warrants that these markers should be used in conjunction with other routine cancer indicators. The present article concludes that such studies can spur development of novel microbiome based cancer diagnostics.

Neoplasms

microbiology

350915

Diagnostic accuracy of non-contrast abdominal CT scans performed as follow-up for patients with an established cancer diagnosis: a retrospective study

Abstract Objectives: To determine the accuracy and non-detection rate of cancer related findings (CRFs) on follow-up non-contrast-enhanced CT (NECT) versus contrast-enhanced CT (CECT) images of the abdomen in patients with a known cancer diagnosis. Methods: A retrospective review of 352 consecutive CTs of the abdomen performed with and without IV contrast between March 2010 and October 2014 for follow-up of cancer was included. Two radiologists independently assessed the NECT portions of the studies. The reader was provided the primary cancer diagnosis and access to the most recent prior NECT study. The accuracy and non-detection rates were determined by comparing our results to the archived reports as a gold standard. Results: A total of 383 CRFs were found in the archived reports of the 352 abdominal CTs. The average non-detection rate for the NECTs compared to the CECTs was 3.0% (11.5/383) with an accuracy of 97.0% (371.5/383) in identifying CRFs. The most common findings missed were vascular thrombosis with a non-detection rate of 100%. The accuracy for non-vascular CRFs was 99.1%. Conclusion: Follow-up NECT abdomen studies are highly accurate in the detection of CRFs in patients with an established cancer diagnosis, except in cases where vascular involvement is suspected.

Neoplasms

diagnostic imaging

98064

Homeoprotein Six2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression.

Misexpression of developmental transcription factors occurs often in human cancers, where embryonic programs may be reinstated in a context that promotes or sustains malignant development. In this study, we report the involvement of the kidney development transcription factor Six2 in the metastatic progression of human breast cancer. We found that Six2 promoted breast cancer metastasis by a novel mechanism involving both transcriptional and epigenetic regulation of E-cadherin. Downregulation of E-cadherin by Six2 was necessary for its ability to increase soft agar growth and in vivo metastasis in an immunocompetent mouse model of breast cancer. Mechanistic investigations showed that Six2 represses E-cadherin expression by upregulating Zeb2, in part, through a microRNA-mediated mechanism and by stimulating promoter methylation of the E-cadherin gene (Cdh1). Clinically, SIX2 expression correlated inversely with CDH1 expression in human breast cancer specimens, corroborating the disease relevance of their interaction. Our findings establish Six2 as a regulator of metastasis in human breast cancers and demonstrate an epigenetic function for SIX family transcription factors in metastatic progression through the regulation of E-cadherin.

Breast Neoplasms

genetics

19661996

Propagation and recovery of intact, infectious Epstein-Barr virus from prokaryotic to human cells.

With current techniques, genetic alterations of herpesviruses are difficult to perform, mostly because of the large size of their genomes. To solve this problem, we have designed a system that allows the cloning of any gamma-herpesvirus in Escherichia coli onto an F factor-derived plasmid. Immortalized B cell lines were readily established with recombinant Epstein-Barr virus (EBV), demonstrating that the F factor-cloned EBV genome has all the characteristics of wild-type EBV. Because any genetic modification is possible in E. coli, this experimental approach opens the way to the genetic analysis of all EBV functions. Moreover, it is now feasible to generate attenuated EBV strains in vitro such that vaccine strains can be designed. Because we incorporated the genes for hygromycin resistance and green fluorescent protein onto the E. coli cloned EBV genome, the still open question of the EBV target cells other than B lymphocytes will be addressed.

Escherichia coli

virology

5666364

Age effects on glycosylated blood proteins in lean and obese hyperglycaemic (ob/ob) mice.

Glycosylated haemoglobins and glycosylated plasma proteins were measured by affinity chromatography using Glycogel B, in 2-40 weeks old lean (+/+) and Aston obese hyperglycaemic (ob/ob) mice, and compared with changes in glucose concentrations. Lean mice showed an increase in glycaemia at weaning (3 weeks), and a small rise thereafter. In comparison with lean mice, ob/ob mice showed decreased glucose concentrations at 2 weeks, euglycaemia at 3-6 weeks, and hyperglycaemia from 7 weeks. The increases in glycaemia were followed by elevations of glycosylated haemoglobins after 1 week in ob/ob mice and 2 weeks in lean mice. Glycosylated haemoglobins were significantly elevated in ob/ob mice at 8-40 weeks. The glycosylated haemoglobins and glucose concentrations were correlated (r = +0.7; p less than 0.01; n = 96) for all mice studied. There was no correlation between glycosylated plasma proteins and glucose, or between glycosylated plasma proteins and glycosylated haemoglobins. Glycosylated plasma proteins were unchanged with age in lean mice, and were not significantly raised in ob/ob mice. The results indicate that glycosylated plasma proteins are a poor indicator of the glycaemic environment in mice due to their rapid turnover. In contrast, measurement of glycosylated haemoglobins provides a convenient and reliable assessment of blood glucose homeostasis in the preceding 1-2 weeks.

Obesity

blood

11306637

Posttransplant CD30+ Anaplastic Large Cell Lymphoma with Skin and Lymph Node Involvement

Posttransplant (i.e. status with the transplant present) lymphoproliferative disorders (PTLD) are common conditions in transplant recipients. Most examples are of B cell origin, and CD30+ T cell PTLD are very rare. We report a CD30+ anaplastic large cell lymphoma (ALCL) in the skin of the right lower leg and in draining lymph nodes of the right inguinal region in an immunosuppressed 59-year-old male who had received a renal graft 9 years previously. Unlike the vast majority of PTLD, an incomplete T cell immunophenotype was observed, and there was evidence of T cell lineage at the genetic level reflected by a rearranged T cell receptor γ gene. The neoplastic cells were non-reactive to the anaplastic lymphoma kinase (ALK) 1 protein. In addition, Epstein-Barr virus and human herpesvirus 8 sequences were absent. Arguments against a primary cutaneous ALCL, which is also ALK-1 negative, include systemic presentation at the time of initial diagnosis and immunoreactivity of the neoplastic cells to epithelial membrane antigen. Typically, our rare example of a posttransplantation systemic ALCL showed an aggressive behaviour and a poor response to both chemotherapy and local irradiation.

Skin Neoplasms

pathology

1659256

Fas/FasL Pathway Participates in Regulation of Antiviral and Inflammatory Response during Mousepox Infection of Lungs

Fas receptor-Fas ligand (FasL) signalling is involved in apoptosis of immune cells as well as of the virus infected target cells but increasing evidence accumulates on Fas as a mediator of apoptosis-independent processes such as induction of activating and proinflammatory signals. In this study, we examined the role of Fas/FasL pathway in inflammatory and antiviral response in lungs using a mousepox model applied to C57BL6/J, B6. MRL-Faslpr/J, and B6Smn.C3-Faslgld/J mice. Ectromelia virus (ECTV) infection of Fas- and FasL-deficient mice led to increased virus titers in lungs and decreased migration of IFN-γ expressing NK cells, CD4+ T cells, CD8+ T cells, and decreased IL-15 expression. The lungs of ECTV-infected Fas- and FasL-deficient mice showed significant inflammation during later phases of infection accompanied by decreased expression of anti-inflammatory IL-10 and TGF-β1 cytokines and disturbances in CXCL1 and CXCL9 expression. Experiments in vitro demonstrated that ECTV-infected cultures of epithelial cells, but not macrophages, upregulate Fas and FasL and are susceptible to Fas-induced apoptosis. Our study demonstrates that Fas/FasL pathway during ECTV infection of the lungs plays an important role in controlling local inflammatory response and mounting of antiviral response.

Lung

immunology

23219991

Advanced maternal age. Part II: long-term consequences.

In addition to the possible association between pregnancy in women with advanced maternal age and increased rates of obstetric and perinatal complications, those women and their children might suffer from long-term sequelae. In this review, the long-term consequences of delayed motherhood on the offspring and the possible association between advanced maternal age and the development of certain cancers are discussed.

Neoplasms

etiology

35112091

NopA is associated with cell surface appendages produced by the type III secretion system of Rhizobium sp. strain NGR234.

Rhizobium sp. strain NGR234, which is capable of interacting with a large number of legumes, utilizes a variety of signaling molecules to establish nitrogen-fixing symbioses. Among these are nodulation outer proteins (Nops) that transit through a type III secretion system (TTSS). Abolition of Nop secretion affects nodulation of certain legumes. Under free-living conditions, the secretion of Nops can be induced by the addition of flavonoids. Here, we show that an in-frame deletion of nopA abolishes secretion of all other Nops and has the same impact on nodule formation as mutations that lead to a nonfunctional TTSS. This secretion-minus phenotype of the nopA mutant, as well as bioinformatics analysis of NopA itself, suggests that NopA could be an external component of the TTSS. Electron microscopy showed that NGR234 synthesizes fibrillar structures on the cell surface in a flavonoid-inducible and NopA-dependent manner. Purification of the macromolecular surface appendages revealed that NopA is a major component of these structures.

Bacterial Proteins

physiology

42627864

Identifying colorectal metastases in liver biopsies: the novel CDX2 antibody is less specific than the cytokeratin 20+/7- phenotype.

BACKGROUND Immunohistochemistry plays an important role in tracing the primary site in metastatic tumors of unknown origin. Therefore, determining the cytokeratin (CK) 20/CK7 pattern of metastases is one of the most helpful procedures as the CK20+/CK7- pattern is typical of colorectal adenocarcinomas. Expression of CDX2 protein is a new, highly specific and sensitive marker of the intestinal origin of adenocarcinomas. In the present study we compared the sensitivity and specificity of CDX2 expression and the CK20+/CK7- phenotype in predicting the colorectal origin of liver metastases. MATERIAL/METHODS The study was carried out on a consecutive series of 125 core-needle biopsies of metastatic adenocarcinomas of the liver. Most of the patients were followed up to death, and primary tumor localization could be established in 102 cases by a combination of clinical, radiological, histological and, in some cases, autopsy data. All the needle biopsies were immunohistochemically stained for CK7, CK20 and CDX2. CDX2 expression (at 10% and 50% cut-off levels) and the CK20/CK7 pattern of the metastases were correlated to the primary site established. RESULTS The CK20+/CK7- pattern showed a specificity of 98.7% in predicting colorectal primary localization, which was superior to that of CDX2 expression at both cut-off levels (90% and 95.3% respectively). The sensitivity of CDX2 expression in these circumstances was 84% at the 10% cut-off, somewhat higher than that of the CK20+/CK7- phenotype (79.5%), but lower at the 50% cut-off level (72.7%). CONCLUSIONS The CK20+/CK7- immunophenotype is more specific in predicting the colorectal origin of liver metastasis than CDX2 expression.

Liver Neoplasms

secondary

994516

Estrogen receptor analysis on needle aspirates from human mammary carcinoma.

Immediately after mastectomy, estrogen receptor concentration was measured in fine needle aspirates and in histologic tissue specimens from 13 human breast carcinomas. Fine needle aspirates were shown to contain enough material for receptor analysis when the sensitive method of isoelectric focusing in slabs of polyacrylamide gel was used for receptor determination. Aspirations with two different needles (outer diameter 0.7 and 1.4 mm) from each tumor yielded highly correlated receptor values (r = 0.97, p less than 0.0001). There was also a highly significant correlation (r = 0.91, p less than 0.0001) between the receptor content in needle aspirates and in tissue specimens from the same tumor.

Breast Neoplasms

metabolism

2585264

ICRF-159 (razoxane) in the treatment of pediatric solid tumors: a Southwest Oncology Group study.

ICRF-159 is active in several animal tumor model systems and human adult malignancies. In this phase II study, ICRF-159 was given on a weekly schedule, 3000 mg/m2/day, orally in three divided doses at 6-hour intervals to 78 children with a variety of malignant neoplasms. Fifty-three patients were evaluable for tumor response. Toxicity was primarily hematopoietic and gastrointestinal. There were no responses in any of the eight patients with osteogenic sarcoma, four with lymphoma, five with Ewing's sarcoma, ten with neuroblastoma, or six with rhabdomyosarcoma. There was a transient partial response in one of four children with Wilms' tumor. Further trials with this drug using this schedule are not indicated for the common childhood solid tumors.

Neoplasms

drug therapy

78094994

Extracellular production of the recombinant bacterial transglutaminase in Pichia pastoris.

Microbial pro-transglutaminase (pro-MTGase) from Streptomyces mobaraensis was expressed in Pichia pastoris (Komagataella phaffii) under the control of constitutive GAP promoter. The single copy of the gene containing clone was grown in shake flasks to determine the optimum conditions for the production of recombinant pro-MTGase. Three temperature (20 °C, 25 °C, 28 °C) and four pH (5, 6, 7, 7.5) values were evaluated at the shake flask level for the extracellular production of pro-MTGase. The highest enzyme activity was obtained with low temperature (20 °C) and high pH (7.5). The maximum yield was 9120 U/L. For the large-scale extracellular production of pro-MTGase, the clone was cultivated in 5 L bioreactor. The fermentation process was carried out at 20 °C, pH 7 and 20% dissolved oxygen for 79 h. The enzyme activity was calculated as 37640 U/L for large-scale production. These results indicate that P. pastoris expression system is very suitable for recombinant MTGase production under the control of the GAP promoter.

Bacterial Proteins

chemistry

3094722

DNA N6-methyladenine in metazoans: functional epigenetic mark or bystander?

The DNA-adenine modification N6-methyladenine (6mA), initially thought to be mainly restricted to prokaryotes and certain unicellular eukaryotes, has recently been found in metazoans. Proposed functions vary from gene activation to transposon suppression. However, since most metazoan genomes possess 5-methylcytosine (5mC) as a dominant epigenetic mark, it raises the question of why 6mA is required. This Perspective summarizes the latest discoveries and suggests potential functional roles for 6mA in metazoan genomes.

DNA

metabolism

23068672

Purification of a new, calcium-independent, high molecular weight phospholipase A2/lysophospholipase (phospholipase B) from guinea pig intestinal brush-border membrane.

A phospholipase A2 activity directed against phosphatidylcholine was previously described in brush-border membrane from guinea pig intestine (Diagne, A., Mitjavila, S., Fauvel, J., Chap, H., and Douste-Blazy, L. (1987) Lipids 22, 33-40). In the present study, this enzyme was solubilized either with Triton X-100 or upon papain treatment, suggesting a structural similarity with other intestinal hydrolases such as leucine aminopeptidase, sucrase, or trehalase. The papain-solubilized form, which is thought to lack the short hydrophobic tail responsible for membrane anchoring, was purified 1800-fold to about 90% purity by ion exchange chromatography on DEAE-Sephacel, gel filtration on Ultrogel AcA44, and hydrophobic chromatography on phenyl-Sepharose. Upon polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate, a main band with an apparent molecular mass of 97 kDa was detected under reducing and nonreducing conditions. In the latter case, phospholipase A2 activity could be recovered from the gel and was shown to coincide with the 97-kDa protein detected by silver staining. The enzyme activity was unaffected by EGTA and slightly inhibited by CaCl2. The purified enzyme displayed a similar activity against phosphatidylcholine and phosphatidylethanolamine, whereas 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine hydrolysis was reduced by 50% compared to diacylglycerophospholipids. Using phosphatidylcholine labeled with either [3H]palmitic acid or [14C]linoleic acid in the 1- or 2-positions, respectively, the purified enzyme catalyzed the removal of [3H]palmitic acid, although at a lower rate compared to [14C]linoleic acid. This resulted in the formation of sn-glycero-3-phosphocholine, but only 1-[3H]palmitoyl-sn-glycero-3-phosphocholine was detected as an intermediary product. In agreement with this, 1-acyl-2-lyso-sn-[14C]glycero-3-phosphocholine was deacylated at almost the same rate as the sn-2-position of phosphatidylcholine. Since upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the two hydrolytic activities were detected at the same position as 97-kDa protein, the enzyme is thus considered as a phospholipase A2 with lysophospholipase activity (phospholipase B), which might be involved in phospholipid digestion.

Calcium

physiology

23990509

Clinicopathological features of type AB thymoma with liver metastases.

OBJECTIVE We studied the clinicopathological features of type AB thymoma with liver metastases and explore the histological types, diagnosis and differential diagnosis, treatment and prognosis for this disease. METHODS Liver metastasis specimens were derived from one case of type AB thymoma 5 years after operation and were examined histologically using light microscopy and immunohistochemistry. A comprehensive analysis was performed on the patient's clinical manifestations, histopathology, immunohistochemistry features, differential diagnosis, treatment and prognosis in combination with a review of the relevant literature. RESULTS Metastases were detected 5 years after initial operation on a 49-year-old, female patient with type AB thymoma. The pathological diagnosis for the liver metastases was type AB thymoma. Immunohistochemistry staining showed CKpan (+), CD3 (+), CD2 (+), TdT (+), CD5 (+), P53 (+), Hep-1 (-), and Ki67-positive cells (25%). The expression level of galectin-3 was higher than in the mediastinal thymoma tissue identified 5 years prior. CONCLUSION Liver metastases of type AB thymoma are extremely rare. This case indicated that type AB thymoma with low malignant potential might recur and develop distant metastases. Overexpression of p53, galectin-3 and Ki67 in type AB thymoma might coordinately manipulate the process of development, progression and malignant transformation of type AB thymomas.

Liver Neoplasms

secondary

77696163

[Morphological changes in the liver of patients with pulmonary tuberculosis--carriers of hepatitis B virus].

: Findings of morphologic studies of the liver bioptic material taken from 42 patients with different forms of pulmonary tuberculosis, hosts of Hbs-antigen, are described. It appears that marked dystrophic, inflammatory and necrotic changes occur in patients of this category, which should be taken into account when etiotropic and pathogenetic therapy is chosen.

Liver

pathology

26648526

Effects of beclomethasone and factors related to asthma on the growth of prepubertal children.

Few studies on the concomitant effects of beclomethasone dipropionate and asthma-related factors on the growth of prepubertal asthmatic children have been published to date. In this prospective long-term 'real-life' cohort study we recruited 82 prepubertal steroid-naïve asthmatic patients aged 3 + years, excluding those with birth weight lower than 2500 g, malnutrition, and other concurrent chronic diseases. Height/age and weight/age Z scores were calculated every three months. Random effects multivariate longitudinal data analysis was used to adjust height/age and weight/age Z scores with independent variables. Among the studied patients, 63.4% were male, aged 4.7 + or - 1.5 years, 68.3% suffered from severe persistent asthma and had normal values for height/age and weight/age Z scores at enrolment. They were followed for 5.2 years (range 2.3-6.1) and used a mean daily beclomethasone dipropionate dose of 351.8 mcg (range 137.3-1140.0). Height/age and weight/age Z scores were not affected by either duration of treatment or doses of beclomethasone dipropionate up to 500 mcg, 750 mcg and higher than 750 mcg (p-values > 0.17). The multivariate analysis final model showed that severe persistent asthma was associated to lower height for age Z score (p = 0.04), whereas hospitalizations because of acute asthma (before and during follow-up) were associated (p = 0.02) to lower weight for age Z score. Growth parameters were not affected by the use of beclomethasone dipropionate.

Asthma

drug therapy

36050034

Mechanism of downregulation of photosystem I content under high-light conditions in the cyanobacterium Synechocystis sp. PCC 6803.

Downregulation of photosystem I (PSI) content is an essential process for cyanobacteria to grow under high-light (HL) conditions. In a pmgA (sll1968) mutant of Synechocystis sp. PCC 6803, the levels of PSI content, chlorophyll and transcripts of the psaAB genes encoding reaction-centre subunits of PSI could not be maintained low during HL incubation, although the causal relationship among these phenotypes remains unknown. In this study, we modulated the activity of psaAB transcription or that of chlorophyll synthesis to estimate their contribution to the regulation of PSI content under HL conditions. Analysis of the psaAB-OX strain, in which the psaAB genes were overexpressed under HL conditions, revealed that the amount of psaAB transcript could not affect PSI content by itself. Suppression of chlorophyll synthesis by an inhibitor, laevulinic acid, in the pmgA mutant revealed that chlorophyll availability could be a determinant of PSI content under HL. It was also suggested that chlorophyll content under HL conditions is mainly regulated at the level of 5-aminolaevulinic acid synthesis. We conclude that, upon the shift to HL conditions, activities of psaAB transcription and of 5-aminolaevulinic acid synthesis are strictly downregulated by regulatory mechanism(s) independent of PmgA during the first 6 h, and then a PmgA-mediated regulatory mechanism becomes active after 6 h onward of HL incubation to maintain these activities at a low level.

Bacterial Proteins

metabolism

23258668

General principles of therapy of pyogenic meningitis.

In bacterial meningitis, several pharmacodynamic factors determine therapeutic success-when defined as sterilization of the CSF: (1) Local host defense deficits in the CNS require the use of bactericidal antibiotics to sterilize the CSF. (2) CSF antibiotic concentrations that are at least 10-fold above the MBC are necessary for maximal bactericidal activity. Protein binding, low pH, and slow bacterial growth rates are among the factors that may explain the high antibiotic concentrations necessary in vivo. (3) High CSF peak concentrations that lead to rapid bacterial killing appear more important than prolonged suprainhibitory concentrations, probably because very low residual levels in the CSF prevent bacterial regrowth, even during relatively long dosing intervals. (4) Penetration of antibiotics into the CSF is significantly impaired by the blood-brain barrier and thus, very high serum levels are necessary to achieve the CSF concentrations required for optimal bactericidal activity. Beyond these principles, recent data suggests that rapid lytic killing of bacteria in the CSF may have harmful effects on the brain because of the release of biologically active products from the lysed bacteria. Since rapid CSF sterilization remains a key therapeutic goal, the harmful consequences of bacterial lysis present a major challenge in the therapy of bacterial meningitis. Currently, dexamethasone represents that only clinically beneficial approach to reduce the harmful effects of bacterial lysis, and novel approaches are required to improve the outcome of this serious infection.

Anti-Bacterial Agents

therapeutic use

41507281

Capillary electrophoretic separation of uncharged polymers using polyelectrolyte engines. Theoretical model.

We recently demonstrated that the molecular mass distribution of an uncharged polymer sample can be analyzed using free-solution capillary electrophoresis of DNA-polymer conjugates. In these conjugates, the DNA is providing the electromotive force while the uncharged polydisperse polymer chains of the sample retard the DNA engine with different amounts of hydrodynamic drag. Here we present a theoretical model of this new analytical method. We show that for the most favourable, diffusion-limited electrophoresis conditions, there is actually an optimal DNA size to achieve the separation of a given polymer sample. Moreover, we demonstrate that the effective friction coefficient of the polymer chains is related to the stiffness of the two polymers of the conjugate, thus offering a method to estimate the persistence length of the uncharged polymer through mobility measurements. Finally, we compare some of our predictions with available experimental results.

DNA

isolation & purification

11043766

Exploiting the properties of biomolecules for brain targeting of nanoparticulate systems.

The main obstacle in the treatment of central nervous system diseases is represented by a limited passage of diagnostic and therapeutic agents across the blood-brain barrier, which separates the blood stream from the cerebral parenchyma and maintains the homeostasis of the brain. The growing knowledge about the brain capillary endothelium and the discovery of specific mechanisms for the uptake of substances enables the development of various strategies to enhance the drug delivery rate into the brain. Among the different strategies, nanoparticles are promising candidates for drug delivery to the brain due to their potential in encapsulating drugs and thereby disguising their permeation limiting characteristics. Furthermore a surface functionalization of many nanoparticles can easily be achieved allowing the active targeting of nanoparticles to the brain. For this non-invasive approach, the surface functionalization of nanoparticles with biomolecules has shown promising potential for effective drug delivery to the brain. This review indexes the main classes of biomolecules used for the surface functionalization of nanoparticles and discusses their potential as drug delivery systems for an enhanced passage of diagnostic and therapeutic agents into the brain parenchyma.

Brain

metabolism

21370374

Hashimoto's thyroiditis and breast cancer.

The question of a possible association between Hashimoto's thyroiditis and breast cancer was evaluated in (1) an autopsy series and (2) a follow-up of a cohort of patients with Hashimoto's thyroiditis at the Mayo Clinic. In the autopsy study, 174 subjects with histologic diagnosis of Hashimoto's thyroiditis were matched with a control group. There was no significant difference in the frequency of a history of breast cancer in the two groups. In the cohort of Olmsted County residents with a clinical or histologic diagnosis of Hashimoto's thyroiditis for whom there was a substantial period of follow-up, no excess frequency of breast cancer was note. These results contrast with those of a recent study reporting that Japanese women with Hashimoto's thyroiditis were a high risk group for breast cancer.

Breast Neoplasms

epidemiology

22488344

Estimation of risk for plantar foot ulceration in diabetic patients with neuropathy.

The main risk factors for plantar forefoot ulcers are loss of protective sensation due to sensory neuropathy and increased mechanical stress on the sole of the foot. The aim of this study was to find a better parameter than the plantar pressure to explain the occurrence of plantar ulcers under the metatarsalheads (MTHs). Twenty diabetic patients (3 Type 1 and 17 Type 2) each with 1 plantar ulcer and 23 Type 2 diabetic patients without plantar ulceration (controls), were investigated. The parameters of plantar pressure, length of contact time and pressure-time integral (PTI) were determined by pedography at defined foot regions. PTI represents the duration of mechanical stress on the foot. Based on the distribution of ulcers, the ratio of stress on the MTHs to that on the big toe was calculated. In diabetic patients with ulcers the difference of PTI between MTHs and hallux was higher at 153% and hence 3.2 times greater than the difference in plantar pressure between MTHs and hallux of 47.3%. In the control group the ratio of difference had a factor of 2 only because the corresponding difference in PTI was 85.1% and the difference in plantar pressure was 43.1%. These results may indicate that increased stress at the MTHs is responsible for the occurrence of planar ulcers compared with other regions of the sole. Diabetic patients with elevated PTI ratio are at risk of developing foot ulcers and therefore have to be provided with orthopaedic shoes to prevent foot ulceration.

Diabetes Mellitus, Type 2

complications

3878416

Molecular profiling reveals primary mesothelioma cell lines recapitulate human disease

Malignant mesothelioma (MM) is an aggressive, fatal tumor strongly associated with asbestos exposure. There is an urgent need to improve MM patient outcomes and this requires functionally validated pre-clinical models. Mesothelioma-derived cell lines provide an essential and relatively robust tool and remain among the most widely used systems for candidate drug evaluation. Although a number of cell lines are commercially available, a detailed comparison of these commercial lines with freshly derived primary tumor cells to validate their suitability as pre-clinical models is lacking. To address this, patient-derived primary mesothelioma cell lines were established and characterized using complementary multidisciplinary approaches and bioinformatic analysis. Clinical markers of mesothelioma, transcriptional and metabolic profiles, as well as the status of p53 and the tumor suppressor genes CDKN2A and NF2, were examined in primary cell lines and in two widely used commercial lines. Expression of MM-associated markers, as well as the status of CDKN2A, NF2, the ‘gatekeeper’ in MM development, and their products demonstrated that primary cell lines are more representative of the tumor close to its native state and show a degree of molecular diversity, thus capturing the disease heterogeneity in a patient cohort. Molecular profiling revealed a significantly different transcriptome and marked metabolic shift towards a greater glycolytic phenotype in commercial compared with primary cell lines. Our results highlight that multiple, appropriately characterised, patient-derived tumor cell lines are required to enable concurrent evaluation of molecular profiles versus drug response. Furthermore, application of this approach to other difficult-to-treat tumors would generate improved cellular models for pre-clinical evaluation of novel targeted therapies.

Lung Neoplasms

metabolism

21469038

Relationships between cholinergic phenotype and acetyl‐CoA level in hybrid murine neuroblastoma cells of septal origin

High susceptibility of cholinergic neurons to neurotoxic signals may result from their utilization of acetyl‐CoA for both energy production and acetylcholine synthesis. SN56 cholinergic cells were transfected stably with cDNA for choline acetyltransferase. Transfected cells (SN56ChAT2) expressed choline acetyltransferase activity and acetylcholine content, 17 times and 2 times higher, respectively, than did nontransfected cells. Transfection did not change pyruvate dehydrogenase but decreased the acetyl‐CoA level by 62%. Differentiation by cAMP and retinoic acid caused an increase of choline acetyltransferase activity and decrease of acetyl‐CoA levels in both cell lines. Negative correlation was found between choline acetyltransferase activity and acetyl‐CoA level in these cells. SN56ChAT2 cells were more susceptible to excess NO than were native SN56 cells, as evidenced by the thiazolyl blue reduction assay. Thus, the sensitivity of cholinergic neurons to pathologic conditions may depend on the cholinergic phenotype‐dependent availability of acetyl‐CoA. © 2003 Wiley‐Liss, Inc.

Neurons

physiology

10984244

Synthesis, characterization, crystal structures and in vitro antistaphylococcal activity of organotin(IV) derivatives with 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidine.

New organotin(IV) complexes of 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp) and 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp) with 1:1 and/or 1:2 stoichiometry were synthesized and investigated by X-ray diffraction, FT-IR and (119)Sn Mössbauer in the solid state and by (1)H and (13)C NMR spectroscopy, in solution. Moreover, the crystal and molecular structures of Et(2)SnCl(2)(dbtp)(2) and Ph(2)SnCl(2)(EtOH)(2)(dptp)(2) are reported. The complexes contain hexacoordinated tin atoms: in Et(2)SnCl(2)(dbtp)(2) two 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine molecules coordinate classically the tin atom through N(3) atom and the coordination around the tin atom shows a skew trapezoidal structure with axial ethyl groups. In Ph(2)SnCl(2)(EtOH)(2)(dptp)(2) two ethanol molecules coordinate tin through the oxygen atom and the 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine molecules are not directly bound to the metal center but strictly H-bonded, through N(3), to the OH group of the ethanol moieties; Ph(2)SnCl(2)(EtOH)(2)(dptp)(2) has an all-trans structure and the C-Sn-C fragment is linear. On the basis of Mössbauer data, the 1:2 diorganotin(IV) complexes are advanced to have the same structure of Et(2)SnCl(2)(dbtp)(2), while Me(2)SnCl(2)(dptp)(2) to have a regular all-trans octahedral structure. A distorted cis-R(2) trigonal bipyramidal structure is assigned to 1:1 diorganotin(IV) complexes. The in vitro antibacterial activities of the synthesized complexes have been tested against a group of reference pathogen micro-organisms and some of them resulted active with MIC values of 5μg/mL, most of all against staphylococcal strains, which shows their inhibitory effect.

Anti-Bacterial Agents

chemistry

64285850

Enhanced adherence counselling and viral load suppression in HIV seropositive patients with an initial high viral load in Harare, Zimbabwe: Operational issues

Background In people living with HIV (PLHIV) who are on anti-retroviral therapy (ART), it is essential to identify persons with high blood viral loads (VLs) (≥1000 copies/ml), provide enhanced adherence counselling (EAC) for 3 months and assess for VL suppression (<1000 copies/ml). Objective Our study objectives were to determine the proportion who had a high viral load in those people who underwent viral load testing between 1 August 2016–31 July 2017 at Wilkins Hospital, Harare, Zimbabwe. Of those with high viral load to assess; a) the proportion who enrolled for EAC, the demographic and clinical characteristics associated with enrolment for EAC and, b) the proportion who achieved viral load suppression and demographic, clinical characteristics associated with viral load suppression. Design Retrospective cohort study using routinely collected programme data. Data was collected from PLHIV who were on ART and had a high viral load from 1 August 2016 to 31 July 2017. Results Of 5,573 PLHIV on ART between 1 August 2016 and 31 July 2017, 4787 (85.9%) had undergone VL testing and 646 (13.5%) had high VLs. Of these 646, only 489 (75.7%) were enrolled for EAC, of whom 444 (69%) underwent a repeat VL test at ≥ 3 months with 201 (31.2%) achieving VL suppression. The clinical characteristics that were independently associated with higher probability of VL suppression were: a) undergoing 3 sessions of EAC; b) being on 2nd line ART. Initial VL levels >5,000 copies/ml were associated with lower probability of viral suppression. Conclusion The routine VL testing levels were high, but there were major programmatic gaps in enrolling PLHIV with high VLs into EAC and achieving VL suppression. The full potential of EAC on achieving viral load suppression has not been achieved in this setting. The reasons for these gaps need to be assessed in future research studies and addressed by suitable changes in policies/practices.

HIV Infections

virology

30494496

Melanoma and Rituximab: An Incidental Association?

Rituximab is an anti-CD20 monoclonal antibody increasingly used in haematology and rheumatology, but also in internal medicine and dermatology. It has a good tolerance profile without known increased risk of cancer. We report a case of nodular melanoma with a 4.8 mm Breslow thickness that appeared after 2 years of rituximab in a 45-year-old patient with non-Hodgkin lymphoma. Fifteen additional rituximab-associated melanoma cases in 13 patients have been identified in the literature and in the EudraVigilance database. These patients were treated for various indications and had melanomas, often aggressive, initially diagnosed at a metastatic stage in 31% of cases. Our work raises the question of rituximab accountability in melanoma onset in these immunosuppressed patients. A dermatological monitoring seems necessary in patients treated with rituximab, especially in case of risk factors for melanoma. In case of individual melanoma history, the benefit/risk ratio of initiating rituximab therapy should be carefully assessed.

Skin Neoplasms

chemically induced

40363834

On the aetiology of hypertrophic pulmonary osteoarthropathy in bronchogenic carcinoma: lack of relationship to elevated growth hormone levels.

Summary: The hypothesis that growth hormone (GH) may be of aetiological importance in hypertrophic pulmonary osteoarthropathy (HPO) and clubbing of the fingers in carcinoma of the lung has been examined. Plasma GH was measured after the oral administration of glucose in 49 patients with carcinoma of the lung with and without HPO and clubbing and the levels were compared with those in age matched control subjects. GH levels were higher in male patients with cancer at 90 and 120 minutes after glucose. In 53% of patients with cancer, GH failed to suppress below 5 ng/ml 90 minutes after glucose, compared with 24% of controls (p < 0.005). There was no correlation between abnormalities of GH metabolism and the presence of HPO or clubbing, and it is suggested that while some tumours produce GH or a G H-like substance, it is not responsible for these pathological changes.

Lung Neoplasms

blood

207941936

A unified framework for mapping individual interregional high-order morphological connectivity based on regional cortical features from anatomical MRI.

Building individual brain networks form the single volume of anatomical MRI is a challenging task. Furthermore, the high-order connectivity of morphological networks remains unexplored. This paper aimed to investigate the individual high-order morphological connectivity from anatomical MRI. Towards this goal, a unified framework based on six feature distances (euclidean, seuclidean, mahalanobis, cityblock, minkowski, and chebychev) was proposed to derive high-order interregional morphological features. The test-retest datasets and the healthy aging datasets were applied to analyze the reliability and the inter-subject variability of the novel features. In addition, the predictive models based on these novel features were established for age estimation. The proposed six neuroanatomical features exhibited significant high-to-excellent reliability. Certain connections were significantly correlated to biological age based on the six novel metrics (p < .05, FDR corrected). Moreover, the predicted age were significantly correlated to the original age in each regression task (r > 0.5, p < 10-6). The results suggested that the novel high-order metrics were reliable and could reflect individual differences, which could be beneficial for current methods of individual brain connectomes.

Brain

anatomy & histology

4852214

A DAQ-Device-Based Continuous Wave Near-Infrared Spectroscopy System for Measuring Human Functional Brain Activity

In the last two decades, functional near-infrared spectroscopy (fNIRS) is getting more and more popular as a neuroimaging technique. The fNIRS instrument can be used to measure local hemodynamic response, which indirectly reflects the functional neural activities in human brain. In this study, an easily implemented way to establish DAQ-device-based fNIRS system was proposed. Basic instrumentation components (light sources driving, signal conditioning, sensors, and optical fiber) of the fNIRS system were described. The digital in-phase and quadrature demodulation method was applied in LabVIEW software to distinguish light sources from different emitters. The effectiveness of the custom-made system was verified by simultaneous measurement with a commercial instrument ETG-4000 during Valsalva maneuver experiment. The light intensity data acquired from two systems were highly correlated for lower wavelength (Pearson's correlation coefficient r = 0.92, P < 0.01) and higher wavelength (r = 0.84, P < 0.01). Further, another mental arithmetic experiment was implemented to detect neural activation in the prefrontal cortex. For 9 participants, significant cerebral activation was detected in 6 subjects (P < 0.05) for oxyhemoglobin and in 8 subjects (P < 0.01) for deoxyhemoglobin.

Brain

physiology

21466635

Glutamate‐mediated astrocyte‐to‐neuron signalling in the rat dorsal horn

By releasing neuroactive agents, including proinflammatory cytokines, prostaglandins and neurotrophins, microglia and astrocytes are proposed to be involved in nociceptive transmission, especially in conditions of persistent, pathological pain. The specific action on dorsal horn neurons of agents released from astrocytes, such as glutamate, has been, however, poorly investigated. By using patch‐clamp and confocal microscope calcium imaging techniques in rat spinal cord slices, we monitored the activity of dorsal horn lamina II neurons following astrocyte activation. Results obtained revealed that stimuli that triggered Ca2+ elevations in astrocytes, such as the purinergic receptor agonist BzATP and low extracellular Ca2+, induce in lamina II neurons slow inward currents (SICs). Similarly to SICs triggered by astrocytic glutamate in neurons from other central nervous system regions, these currents (i) are insensitive to tetrodotoxin (TTX), (ii) are blocked by the NMDA receptor (NMDAR) antagonist d‐AP5, (iii) lack an AMPA component, and (iv) have slow rise and decay times. Ca2+ imaging also revealed that astrocytic glutamate evokes NMDAR‐mediated episodes of synchronous activity in groups of substantia gelatinosa neurons. Importantly, in a model of peripheral inflammation, the development of thermal hyperalgesia and mechanical allodynia was accompanied by a significant increase of spontaneous SICs in dorsal horn neurons. The NMDAR‐mediated astrocyte‐to‐neuron signalling thus represents a novel pathway that may contribute to the control of central sensitization in pathological pain.

Neurons

physiology

209492076

Proton therapy in the most common pediatric non-central nervous system malignancies: an overview of clinical and dosimetric outcomes

Radiation therapy represents an important approach in the therapeutic management of children and adolescents with malignant tumors and its application with modern techniques – including Proton Beam Therapy (PBT) – is of great interest. In particular, potential radiation-induced injuries and secondary malignancies – also associated to the prolonged life expectancy of patients – are still questions of concern that increase the debate on the usefulness of PBT in pediatric treatments. This paper presents a literary review of current applications of PBT in non-Central Nervous System pediatric tumors (such as retinoblastoma, Hodgkin Lymphoma, Wilms tumor, bone and soft tissues sarcomas). We specifically reported clinical results achieved with PBT and dosimetric comparisons between PBT and the most common photon-therapy techniques. The analysis emphasizes that PBT minimizes radiation doses to healthy growing organs, suggesting for reduced risks of late side-effects and radiation-induced secondary malignancies. Extended follow up and confirms by prospective clinical trials should support the effectiveness and long-term tolerance of PBT in the considered setting.

Neoplasms

radiotherapy

33312154

The role of CpG in DNA vaccines

One of the most exciting developments in the field of vaccine research in recent years has been DNA vaccines, with which immune responses are induced sub-sequent to the in vivo expression of antigen from directly introduced plasmid DNA. Strong immune responses have been demonstrated in a number of animal models against many viral, bacterial and parasitic pathogens, and several human clinical trials have been undertaken. The strong and long-lasting antigen-specific humoral (antibodies) and cell-mediated (T help, other cytokine functions and cytotoxic T cells) immune responses induced by DNA vaccines appear to be due to the sustained in vivo expression of antigen, efficient antigen presentation and the presence of stimulatory CpG motifs. These features are desirable for the development of prophylactic vaccines against numerous infectious agents. Furthermore, the strong cellular responses are also very desirable for the development of therapeutic DNA vaccines to treat chronic viral infections or cancer. Efforts are now focusing on understanding the mechanisms for the induction of these immune responses, which in turn should aid in the optimization of DNA vaccines. This review will focus on the role of CpG motifs in DNA vaccines.

DNA

immunology

207689518

Activation of AMP-activated kinase modulates sensitivity of glioma cells against epidermal growth factor receptor inhibition.

The epidermal growth factor (EGFR) pathway is frequently activated in glioblastoma but the clinical efficacy of EGFR inhibitors in malignant glioma has been disappointing. The reasons for the failure of the mechanisms of resistance of these inhibitors are unclear, but may involve factors of the tumor microenvironment such as limited glucose availability and hypoxia. It was therefore examined whether glucose and oxygen influenced the response of glioma cells to EGFR inhibition. Decreased levels of glucose and oxygen led to resistance against the EGFR inhibitor PD153035, whereas high glucose amounts and normoxia sensitised glioma cells towards the inhibitor. Low levels of glucose and oxygen stimulated AMP-activated kinase (AMPK) in glioma cells. 2DG, an inhibitor of glycolysis, and the AMPK activator A769662 reduced glucose consumption, induced phosphorylation of AMPK and mimicked the effects of low glucose availability on the toxicity of PD153035. Similarly, 2DG reduced toxicity of imatinib in K562 leukemia cells. In contrast, inhibition of AMPK by compound C or by short-hairpin (sh)-mediated gene suppression increased cell death induced by the EGFR inhibitor and reverted the protective effects of 2DG and A769662. In conclusion, cytotoxicity of EGFR inhibition can be diminished by AMPK activation in glioma cells. These results may provide one explanation for the low activity of EGFR inhibitors in clinical trials and suggest antagonism of AMPK or of AMPK-regulated metabolic alterations as a promising approach to enhance their therapeutic efficacy.

Antineoplastic Agents

administration & dosage