Clinical Value of (18)F-FDG- PET-CT in the Preoperative Staging of Peritoneal Carcinomatosis from Colorectal Origin.

BACKGROUND: dequate staging is essential in patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) who are candidates for cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC). Metabolic imaging using (18)F-FDG-PET-CT is commonly used to exclude distant metastasis in these patients. Here, we aimed to assess the performance of (18)F-FDG-PET-CT in locoregional staging of the extent of PC. METHODS: Patients with PC from CRC underwent staging including 18F-FDG-PET-CT. In the absence of systemic -dissemination, CRS and oxaliplatin based HIPEC were performed. The extent of PC was quantified during surgery using the modified 7 region count (7RC). The correlation between imaging based estimation of PC extent and surgical 7RC was analyzed using Pearson correlation using both patient based and region based analyses. RESULTS: Fifty-five patients were included between February 2005 and October 2018. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 57%, 98%, 95%, 78% and 82% respectively for non-mucinous tumors and 32%, 100%, 100%, 55% and 63% respectively. (18)F-FDG-PET-CT detected the presence of colorectal PC in 96% of patients suffering from PC with nonmucinous histology and in 60% of patients suffering from PC with mucinous histology. Correlation between imaging 7RC and surgical 7RC was better for PC with nonmucinous histology (r = 0.623) than for PC with mucinous histology (r = -0.180). CONCLUSIONS: Despite of underestimating the exact extent of disease involvement, (18)F-FDG-PET-CT shows good performance in detecting colorectal PC with nonmucinous histology. For colorectal PC with mucinous histology, (18)F-FDG-PET-CT, however, shows poor performance. Since (18)F-FDG-PET-CT did not detect the presence of colorectal PC in all patients in whom long-term survival could be achieved, (18)F-FDG-PET-CT should be implemented into a broad pre-operative assessment strategy.

The clinical-diagnostic role of antistreptolysin O antibodies.

The antistreptolysin O antibody (ASLO) test is often requested in a clinical setting with limited evidence for its usefulness. For this reason, the diagnostic scenario in which ASLO plays an evidence-based role and the analytical performance of the test are critically appraised, taking into account the clinical need and the direct medical cost. Little or no scientific evidence was found for the use of ASLO in patients with pharyngitis, post-streptococcal glomerulonephritis and in adults with rheumatoid arthritis. The clinical relevance of ASLO is restricted to paediatrics, where it contributes to fulfil the diagnosis of acute rheumatic fever (ARF) as per Jones criteria. The standardization of current automated ASLO-latex assays is limited. Attention should be paid to inaccurate reference values and many circumstances causing false positive and false negative results. Because of a low prevalence of ARF in the Western world, a high negative predictive value is obtained for the ASLO test (> 99%). In clinical practice, the result of the test is not urgent. To reduce overconsumption, the clinical laboratory should drive the request behaviour of physicians by a strategic lay-out of the application form. The health insurance/government also contributed by introducing a diagnostic rule for reimbursement.

Multicenter external quality assessment of molecular methods for detection of human herpesvirus 6.

The purpose of this study was to evaluate the performance of laboratories for the detection and quantification of human herpesvirus 6 (HHV-6) by an external quality assessment (EQA) evaluation. The HHV-6 EQA panel consisted of eight samples containing various concentrations of HHV-6 type A (strain GS) or type B (strain Z29), two samples containing other herpesviruses (i.e., human cytomegalovirus [HCMV] and Epstein-Barr virus [EBV]), and two HHV-6-negative samples. Panel samples were prepared in human plasma, heat inactivated, and lyophilized. Panel distribution, data management, and analysis were coordinated by Quality Control for Molecular Diagnostics (QCMD), Glasgow, United Kingdom. Fifty-one laboratories participated and submitted 57 data sets. Eleven (19.3%) data sets were generated using conventional in-house assays, 11 (19.3%) data sets using commercial real-time PCR assays, and 35 (61.4%) data sets using in-house real-time PCR assays. The presence of HHV-6 DNA at viral loads exceeding 6,000 copies/ml was detected by all participants, and over 80% of the participants still reported correct qualitative results for the sample containing just over 200 copies/ml. The false-positivity rate was 1.8% for both the negative samples and the samples containing HCMV or EBV DNA. The majority (23/33; 69.7%) of quantitative data sets were generated using in-house real-time PCR assays. The standard deviations of the geometric means of the samples ranged from 0.5 to 0.7 log(10). The results of this first international EQA demonstrate encouraging analytical sensitivity for the detection of HHV-6-DNA in human plasma, although we observed extensive interlaboratory variation of quantitative HHV-6 DNA results. Standardization needs to be improved to allow further elucidation of the clinical significance of HHV-6 loads.

Simultaneous detection of human bocavirus and adenovirus by multiplex real-time PCR in a Belgian paediatric population.

Since the discovery of human bocavirus (hBoV), the virus has been detected worldwide in respiratory tract samples from young children by various polymerase chain reaction (PCR) assays and real-time PCRs (Q-PCR). Until now, no data have been reported on the presence of hBoV in Belgium and the detection of hBoV in a multiplex Q-PCR setting has not been described. The aim of this study was to develop a fast and reliable multiplex Q-PCR for the simultaneous detection of hBoV DNA and adenovirus (AdV) DNA. During the winter of 2004-2005, 445 nasopharyngeal aspirates (NPAs) were analysed from 404 Belgian children up to 5 years old with acute respiratory tract infections (ARTIs). (Co)infections with hBoV, AdV, respiratory syncytial virus (RSV), human metapneumovirus (hMPV) and influenza A virus were investigated. A viral agent was detected in 61% (n = 272/445) of the NPAs. Multiplex Q-PCR found a prevalence of 11% (n = 51/445) hBoV and 13% (n = 58/445) AdV. Coinfections were more frequently found with AdV (62%; n = 36/58) than with hBoV (49%; n = 25/51). Follow-up samples were available from 22 patients with ARTIs. In three patients, hBoV DNA persisted for one month. Multiplex Q-PCR may help in closing the diagnostic gap by addressing a broader range of potential respiratory pathogens.

Monitoring of herpes simplex virus in the lower respiratory tract of critically ill patients using real-time PCR: a prospective study.

Herpes simplex virus (HSV) has increasingly been associated with pulmonary disease in critically ill patients. However, the clinical relevance of HSV is still a topic of debate. Monitoring of HSV in a quantitative way could potentially give relevant information on its role in the pathogenesis of lower respiratory tract infection. A fast and reliable quantitative real-time PCR (Q-PCR) for the quantitative detection of HSV-1 and HSV-2 DNA was developed. A prospective observational study was performed in an intensive-care unit (ICU) to monitor the HSV viral load in lower respiratory tract aspirates of long-term mechanically ventilated patients. HSV was common in the lower respiratory tract (LRT) of critically ill patients with mechanical ventilation for at least 48 h (62%, n = 65/105). Detection of HSV was significantly associated with prolonged mechanical ventilation (p <0.01), prolonged ICU stay (p <0.01), and development of ventilator-associated pneumonia (p = 0.02). Corticosteroid administration (p <0.01) in the ICU and anti-HSV IgG seropositivity (p <0.01) were risk factors for the occurrence of HSV in the LRT. The fact that no HSV-seronegative patient became positive suggests that all HSV DNA-positive patients had HSV reactivations. Monitoring the HSV viral load in the LRT of critically ill patients showed a typical homogeneous pattern of HSV kinetics. HSV emerged in tracheal and bronchial aspirates after a median of 7 days of intubation (5-11 days), and this was followed by an exponential increase (c. 1 log copies/mL/day) to reach very high HSV peaks (10(6)-10(10) copies/mL) in 78% of the HSV DNA-positive patients.

Does fluoride rinsing have an effect on teeth status? Evaluation of preventive dental health activities for the youth of Woudenberg, The Netherlands.

Surveys among primary school children of group 8 (mainly 12-year olds) in 1988/1989 and 1995/1996 revealed that the dental status in Woudenberg was worse than in other municipalities in the Eemland region. Therefore, several dental preventive activities were started in Woudenberg for children aged 0-12 years. This included fluoride rinsing and teeth brushing lessons at primary schools. So as to evaluate the effect of these school activities, a new survey was carried out in Woudenberg in 2004. The teeth status (DMF-S value, percentage sound teeth, percentage erosion) was investigated by examination. Information regarding dental hygiene behaviour and participation in teeth brushing lessons was obtained by questionnaire. Teeth status (measured by DMF-S value as well as percentage sound teeth) at rinsing schools in 2004 was significantly better than at the same schools in 1995/1996. Multivariate analyses revealed that fluoride rinsing for at least 3 years (besides educational level of parents) is the most determining factor for teeth status independent of other variables. Pupils who never rinsed with fluoride were almost four times more likely to have caries lesions than pupils who rinsed for at least 3 years. This study strongly indicates that long-term rinsing with fluoride has a positive effect on teeth status.

Pedophilia is accompanied by increased plasma concentrations of catecholamines, in particular epinephrine.

Plasma epinephrine and norepinephrine concentrations were measured in pedophiles and normal men both in placebo conditions and after administration of meta-chlorophenylpiperazine (mCPP), a post-synaptic 5-HT2 receptor agonist. The plasma concentrations of catecholamines, in particular epinephrine, were significantly increased in pedophiles. It is concluded that pedophiles may have an increased activity of the sympathoadrenal system.

Activation of human macrophages by amyloid-beta is attenuated by astrocytes.

In Alzheimer's disease, neuritic amyloid-beta plaques along with surrounding activated microglia and astrocytes are thought to play an important role in the inflammatory events leading to neurodegeneration. Studies have indicated that amyloid-beta can be directly neurotoxic by activating these glial cells to produce oxygen radicals and proinflammatory cytokines. This report shows that, using primary human monocyte-derived macrophages as model cells for microglia, amyloid-beta(1-42) stimulate these macrophages to the production of superoxide anions and TNF-alpha. In contrast, astrocytes do not produce both inflammatory mediators when stimulated with amyloid-beta(1-42). In cocultures with astrocytes and amyloid-beta(1-42)-stimulated macrophages, decreased levels of both superoxide anion and TNF-alpha were detected. These decreased levels of potential neurotoxins were due to binding of amyloid-beta(1-42) to astrocytes since FACScan analysis demonstrated binding of FITC-labeled amyloid-beta(1-42) to astrocytoma cells and pretreatment of astrocytes with amyloid-beta(1-16) prevented the decrease of superoxide anion in cocultures of human astrocytes and amyloid-beta(1-42)-stimulated macrophages. To elucidate an intracellular pathway involved in TNF-alpha secretion, the activation state of NF-kappaB was investigated in macrophages and astrocytoma cells after amyloid-beta(1-42) treatment. Interestingly, although activation of NF-kappaB could not be detected in amyloid-beta-stimulated macrophages, it was readily detected in astrocytoma cells. These results not only demonstrate that amyloid-beta stimulation of astrocytes and macrophages result in different intracellular pathway activation but also indicate that astrocytes attenuate the immune response of macrophages to amyloid-beta(1-42) by interfering with amyloid-beta(1-42) binding to macrophages.

Intracellular pathways involved in TNF-alpha and superoxide anion release by Abeta(1-42)-stimulated primary human macrophages.

In this study, the intracellular signal transduction pathways leading to the production of TNF-alpha and superoxide anions by amyloid-beta-stimulated primary human monocyte-derived macrophages was investigated. Using Western blotting and specific inhibitors it is shown that both ERK 1/2 and p38 MAPK signal transduction pathways as well as PKC are involved in the amyloid-beta-stimulated superoxide anion production. In contrast, only ERK 1/2 MAPK seems to be involved in TNF-alpha production: questioning the connection between PKC and ERK 1/2 activation. Our results suggest the use of ERK 1/2 MAPK inhibitors in the prevention of macrophage activation in the context of Alzheimer's disease.

The prolonged P(300) latency in recently detoxified alcohol-dependent patients is related to activation of the inflammatory response system.

The aims of this study were to examine the late components of the auditory event-related potentials (AERPs), i.e. N(100), P(200) and P(300), in recently detoxified alcohol-dependent patients compared to normal controls and to investigate whether there is a relationship between alterations in these AERPs and signs of activation of the inflammatory response system (IRS). The study subjects consisted of 14 healthy volunteers and 14 recently detoxified alcohol-dependent patients. All subjects performed a two-tone auditory discrimination task, using a standard "oddball" paradigm. The alcohol-dependent patients had their blood sampled to examine IRS markers, such as erythrocyte sedimentation rate (ESR), serum copper concentrations and the number of leukocytes. The P(300) latency was significantly greater in recently detoxified alcohol-dependent patients than in normal controls. There were significant correlations between the P(300) latency and the ESR (r = 0.84, p = 0.009), serum copper concentrations (r = 0.73, p = 0.01) and number of monocytes (r = 0.71, p = 0.006). It is concluded that the P(300) latency is prolonged in detoxified, chronic alcohol-dependent patients and is positively related to indicators of IRS activation. It is hypothesized that activation of the IRS may play a role in the delayed P(300) latency in recently detoxified, alcohol-dependent patients.

Lower baseline plasma cortisol and prolactin together with increased body temperature and higher mCPP-induced cortisol responses in men with pedophilia.

There is some evidence that hormonal and serotonergic alterations may play a role in the pathophysiology of paraphilias. The aims of the present study were to examine: 1) baseline plasma cortisol, plasma prolactin, and body temperature; and 2) cortisol, prolactin, body temperature, as well as behavioral responses to meta-chlorophenylpiperazine (mCPP) and placebo in pedophiles and normal men. Pedophiles showed significantly lower baseline plasma cortisol and prolactin concentrations and a higher body temperature than normal volunteers. The mCPP-induced cortisol responses were significantly greater in pedophiles than in normal volunteers. In normal volunteers, mCPP-induced a hyperthermic response, whereas in pedophiles no such response was observed. mCPP induced different behavioral responses in pedophiles than in normal men. In pedophiles, but not in normal men, mCPP increased the sensations "feeling dizzy, " "restless," and "strange" and decreased the sensation "feeling hungry". The results suggest that there are several serotonergic disturbances in pedophiles. It is hypothesized that the results are compatible with a decreased activity of the serotonergic presynaptic neuron and a 5-HT2 postsynaptic receptor hyperresponsivity.

Lower serum vitamin E concentrations in major depression. Another marker of lowered antioxidant defenses in that illness.

OBJECTIVE: Major depression is associated with defective antioxidant defenses. Vitamin E is the major fat soluble antioxidant in the body. The aim of the present study is to examine serum vitamin E concentrations in major depressed patients versus normal volunteers. METHOD: Serum vitamin E concentrations were measured in 26 healthy volunteers and 42 major depressed patients by means of HPLC. Since vitamin E is a fat soluble vitamin, and serum vitamin E concentrations are strongly related to these of low-density-lipoprotein cholesterol (LDL-C) and triglycerides, we have adjusted the results for possible differences in these lipids. The numbers of peripheral blood leukocytes were measured. RESULTS: Patients with major depression had significantly lower serum vitamin E concentrations than healthy controls. The area under the ROC (receiver operating characteristics) curve was 83%. There were significant and negative correlations between serum vitamin E and number of total leukocytes and neutrophils. CONCLUSIONS: Major depression is accompanied by significantly lower serum vitamin E concentrations, suggesting lower antioxidant defenses against lipid peroxidation. The results could, in part, explain previous findings, which suggest increased lipid peroxidation in major depression.

Hydroxyurea interferes with antigen-dependent T-cell activation in vitro.

BACKGROUND: Hydroxyurea is believed to inhibit human immunodeficiency virus type 1 (HIV-1) in HIV disease by decreasing the amount of intracellular deoxynucleotides needed for viral replication. A plasma concentration of 400 micromol L-1 is tolerated in oncological diseases. The present study focused on the possible interference of hydroxyurea with antigen-dependent T-cell activation as an alternative explanation for inhibiting HIV replication in vivo. METHODS: The effect of hydroxyurea on common antigen-induced cell proliferation was studied in peripheral blood mononuclear cells (PBMC) in vitro. RESULTS: Hydroxyurea inhibited Candida albicans-induced cell proliferation at a low concentration (1 micromol L-1), while at least 10 micromol L-1 was required to block HIV-1 replication in phytohaemagglutinin (PHA)-stimulated PBMC. CONCLUSION: Hydroxyurea inhibits antigen-induced lymphoproliferation in vitro at a concentration at which it does not inhibit PHA-induced HIV replication. Hydroxyurea may inhibit HIV-1 in CD4+ T cells in vivo not only by decreasing the amount of intracellular deoxynucleotides, but more specifically by interfering with antigen-dependent T-cell activation, thereby causing a reduction in the number of HIV target cells.

Targeted disruption of the Cln3 gene provides a mouse model for Batten disease. The Batten Mouse Model Consortium [corrected].

Batten disease, a degenerative neurological disorder with juvenile onset, is the most common form of the neuronal ceroid lipofuscinoses. Mutations in the CLN3 gene cause Batten disease. To facilitate studies of Batten disease pathogenesis and treatment, a murine model was created by targeted disruption of the Cln3 gene. Mice homozygous for the disrupted Cln3 allele had a neuronal storage disorder resembling that seen in Batten disease patients: there was widespread and progressive intracellular accumulation of autofluorescent material that by EM displayed a multilamellar rectilinear/fingerprint appearance. Inclusions contained subunit c of mitochondrial ATP synthase. Mutant animals also showed neuropathological abnormalities with loss of certain cortical interneurons and hypertrophy of many interneuron populations in the hippocampus. Finally, as is true in Batten disease patients, there was increased activity in the brain of the lysosomal protease Cln2/TPP-1. Our findings are evidence that the Cln3-deficient mouse provides a valuable model for studying Batten disease.

The amino-terminus of the amyloid-beta protein is critical for the cellular binding and consequent activation of the respiratory burst of human macrophages.

Here, we show that amyloid-beta (Abeta) is capable to prime and activate the respiratory burst of human macrophages. Previously, the N-terminus of Abeta(1-42) has been shown to contain a cell binding domain that is implicated in eliciting neuropathogenic microglia in vitro. To evaluate the role of this domain in the Abeta(1-42)-induced respiratory burst activity, the effect of Abeta subfragments on the Abeta(1-42)-induced superoxide release were studied. On the basis of the antagonistic properties of Abeta(1-16), it is concluded that the N-terminal region of Abeta is critical for the cellular binding and consequent activation of the respiratory burst of human phagocytes.

A murine model for juvenile NCL: gene targeting of mouse Cln3.

JNCL is a neurodegenerative disease of childhood caused by mutations in the CLN3 gene. A mouse model for JNCL was created by disrupting exons 1-6 of Cln3, resulting in a null allele. Cln3 null mice appear clinically normal at 5 months of age; however, like JNCL patients, they exhibit intracellular accumulation of autofluorescent material. A second approach will generate mice in which exons 7 and 8 of Cln3 are deleted, mimicking the common mutation in JNCL patients.

Lower serum zinc in relation to serum albumin and proinflammatory cytokines in detoxified alcohol-dependent patients without apparent liver disease.

Recently, it was reported that there may be an activation of the inflammatory response system in detoxified alcohol-dependent patients without apparent liver disease (AWLD). The aims of the present study were to examine serum zinc (Zn) concentrations, total serum protein (TSP) and patterns obtained in the electrophoretically separated protein fractions in relation to serum interleukin-6 (IL-6) and IL-8 concentrations in detoxified AWLD patients. Zn, TSP, SP electrophoresis, and serum IL-6 and IL-8 concentrations were determined in detoxified AWLD patients and age-matched healthy volunteers. Serum Zn, TSP and the serum concentrations of albumin (Alb) and the beta fraction were significantly lower in detoxified AWLD patients than in healthy volunteers. The percentage of the alpha2 fraction was significantly higher in detoxified AWLD patients. Lower serum Zn in detoxified AWLD patients was attributable to lowered serum Alb. Lower serum Alb was significantly and negatively correlated to increased serum IL-8. The percentage of the alpha1 and alpha2 fractions were significantly and positively related to serum IL-6 and IL-8. The results show that there is an in vivo activation of the inflammatory response system in detoxified AWLD patients and that lower serum Zn may be causally related to lower serum Alb.

Lower serum zinc in major depression in relation to changes in serum acute phase proteins.

There is now some evidence that major depression is accompanied by activation of the inflammatory response system (IRS). Other signs of IRS activation, which have been reported in major depression are lowered serum zinc (Zn) and serum albumin (Alb) concentrations. In serum, Zn is closely bound to Alb. The aims of the present study were to replicate previous findings that major depression is accompanied by lowered serum Zn and Alb and to examine whether the decrease in serum Zn may be explained by that in serum Alb. The above variables were determined in 48 major depressed patients and in 15 age-sex-matched healthy volunteers. Serum Zn and Alb were significantly lower in major depressed patients than in normal volunteers. In healthy volunteers and major depressed patients, there were significant and positive correlations between serum Zn and Alb. We found that 53.8% of the variance in serum Zn could be explained by the combined effects of serum Alb and diagnostic classification. The results suggest that lower serum Zn in depression is in part explained by lowered serum Alb and by another depression-related mechanism. It is suggested that lower serum Zn in depression may be secondary to sequestration of metallothionein in the liver, which may be related to increased production of interleukin-6.

Induction of HIV-1 IIIb neutralizing antibodies in BALB/c mice by a chimaeric peptide consisting of a T-helper cell epitope of Semliki Forest virus and a B-cell epitope of HIV.

A colinearly synthesized peptide consisting of a H-2d restricted T-helper cell epitope of Semliki Forest virus (SFV) and triple repeats of sequence GPGRAF, derived from the V3 domain of HIV-1 strains, was used to immunize BALB/c (H-2d) mice. Pepscan analysis of sera from peptide-immunized mice revealed that the chimaeric peptide GREKFTIRPHYGKEIGPGRAFGPGRAFGPGRAF contains three distinct antibody-reactive sequences GREKFTIR, PHYGKEI and GPGRAF. The chimaeric peptide evoked HIV-1 IIIb neutralizing antibodies in serum as measured in vitro by reduction of syncytia formation and reduction of p24 production as well. So, the T-helper cell epitope of SFV provided help to a small linear neutralization epitope of HIV-1 strains. Interestingly, the T-helper cell epitope alone might induce antibodies cross-reactive with HIV-1 IIIb specific peptide GPGRAFVTIGK which shows some homology (residues underlined) with the antibody-reactive sequence GREKTIR of SFV.

Activation and cell cycle antigens in CD4+ and CD8+ T cells correlate with plasma human immunodeficiency virus (HIV-1) RNA level in HIV-1 infection.

The relationship between T cell activation and human immunodeficiency virus type 1 (HIV-1) replication was studied in HIV-infected subjects, 20 with and 10 without anti-HIV treatment. Expression of Ki-67 proliferation-associated antigen was increased in CD4+ and CD8+ T cells and correlated with HLA-DR. In subjects without anti-HIV treatment, the plasma HIV-1 RNA level correlated with HLA-DR in CD4+ T cells, with Ki-67 in CD8+ T cells, and with expression of CD38 in both T cell subsets. A proportion of treated subjects had increased T cell activation despite 4 months of highly active antiretroviral treatment (HAART). In subjects receiving HAART, a high percentage of HLA-DR+ CD4+ T cells was associated with signs of opportunistic infections. This work supports the concept that, in the natural course of HIV-1 infection, HIV replication itself leads to general T cell activation and that opportunistic infections generate additional CD4+ T cell activation and HIV replication.