Recruitment of activated neutrophils correlates with disease severity in adult Crohn's disease.

Neutrophils are detected in inflamed colon in Crohn's disease (CD). However, whether the frequency and/or activation of circulating or gut tissue neutrophils correlate with endoscopic severity remains to be investigated. A cohort of 73 CD patients was prospectively enrolled according to endoscopic severity and treatment history. Individuals with active disease were stratified using the Montreal classification. Harvey-Bradshaw Index (HBI) and Simple Endoscopic Score for Crohn's Disease (SES-CD) were performed at the time of ileocolonoscopy. Frequency of neutrophils and their expression of CD66b and CD64 were assessed in paired blood and colonic biopsies using flow cytometry. The percentage of neutrophils increased in inflamed colon and correlated with SES-CD in the entire cohort of patients examined, as well as in the subgroup with inflammatory (B1) active disease. SES-CD further correlated with neutrophil CD66b expression in mucosa but not blood and, conversely, with neutrophil CD64 expression in blood but not mucosa. However, the evaluation of neutrophil activation in mucosa when compared to blood reflected disease activity more clearly. Finally, a neutrophil activation power index (CD66b in mucosa X CD64 in blood) that correlated with SES-CD discriminated between patients with mild and severe disease. In conclusion, the frequency and activation of colonic neutrophils correlated with SES-CD, highlighting that mucosal neutrophils are associated with disease severity in CD.

Homogeneity in immune features between colorectal liver metastases better identifies patients with good prognosis compared to pathological response to preoperative chemotherapy.

In colorectal cancer liver metastases (CRLM), the density of tumor-infiltrating lymphocytes, the expression of class I major histocompatibility complex (MHC-I), and the pathological response to preoperative chemotherapy have been associated with oncological outcomes after complete resection. However, the prognostic significance of the heterogeneity of these features in patients with multiple CRLMs remains under investigation. We used a tissue microarray of 220 mismatch repair-gene proficient CRLMs resected in 97 patients followed prospectively to quantify CD3+ T cells and MHC-I by immunohistochemistry. Histopathological response to preoperative chemotherapy was assessed using standard scoring systems. We tested associations between clinical, immunological, and pathological features with oncologic outcomes. Overall, 29 patients (30.2%) had CRLMs homogeneous for CD3+ T cell infiltration and MHC-I. Patients with immune homogeneous compared to heterogeneous CRLMs had longer median time to recurrence (TTR) (30 vs. 12 months, p = .0018) and disease-specific survival (DSS) (not reached vs. 48 months, p = .0009). At 6 years, 80% of the patients with immune homogeneous CRLMs were still alive. Homogeneity of response to preoperative chemotherapy was seen in 60 (61.9%) and 69 (80.2%) patients according to different grading systems and was not associated with TTR or DSS. CD3 and MHC-I heterogeneity was independent of response to pre-operative chemotherapy and of other clinicopathological variables for their association with oncological outcomes. In patients with multiple CRLMs resected with curative intent, similar adaptive immune features seen across metastases could be more informative than pathological response to pre-operative chemotherapy in predicting oncological outcomes.

Live imaging of Toll-like receptor 2 response in cerebral ischaemia reveals a role of olfactory bulb microglia as modulators of inflammation.

Activation of microglial cells in response to ischaemic injury, inflammatory and/or immune stimuli is associated with the marked induction of Toll-like receptor 2 (TLR2). At present, little is known about the spatial and temporal sequence of events, micro-regional specificities and the potential long term role of the TLR2 response to brain injuries. To investigate microglial activation/TLR2 response in real time, we generated a transgenic mouse model bearing the dual reporter system luciferase/green fluorescent protein under transcriptional control of a murine TLR2 promoter. In this model, transcriptional activation of TLR2 was visualized in the brains of live animals using biophotonic/bioluminescence molecular imaging and a high resolution/sensitivity charged coupled device camera. It was found that TLR2 induction/microglial activation has a marked chronic component after ischaemic injury and may last several months after the initial attack. The pro-inflammatory response was not restricted to the site of ischaemic injury but was also evident in the olfactory bulb. A significant TLR2 response was first seen in the olfactory bulb 6 h after stroke and several hours before the increase in photon emission over the site of infarction. This sequence of events was further confirmed by immunohistochemistry. A similar early TLR2 response from olfactory bulb microglia was observed in the brain's immune response to pathogens. We therefore propose that, owing to their unique situation, receiving and translating numerous inputs from the brain as well as from the environment, olfactory bulb microglia may serve as sensors and/or modulators of brain inflammation.

Methylene blue administration fails to confer neuroprotection in two amyotrophic lateral sclerosis mouse models.

Approximately 20% cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies have shown that methylene blue (MB) was efficient in conferring protection in several neurological disorders. MB was found to improve mitochondrial function, to reduce reactive oxygen species, to clear aggregates of toxic proteins, and to act as a nitric oxide synthase inhibitor. These pleiotropic effects of relevance to ALS pathogenesis led us to test MB in two models of ALS, SOD1(G93A) mice and TDP-43(G348C) transgenic mice. Intraperitoneal administration of MB at two different doses was initiated at the beginning of disease onset, at 90 days of age in SOD1(G93A) and at 6 months of age in TDP-43(G348C) mice. Despite its established neuroprotective properties, MB failed to confer protection in both mouse models of ALS. The lifespan of SOD1(G93A) mice was not affected by MB treatment. The declines in motor function, reflex score, and body weight of SOD1(G93A) mice remained unchanged. MB treatment had no effect on motor neuron loss and aggregation or misfolding of SOD1. A combination of MB with lithium also failed to provide benefits in SOD1(G93A) mice. In TDP-43(G348C) mice, MB failed to improve motor function. Cytosolic translocation of TDP-43, ubiquitination and inflammation remained also unchanged after MB treatment of TDP-43(G348C) mice.

Experimental measurements within a phase change metallurgical reactor.

The measurement of solidification front evolution is essential for the optimization and control of many important metallurgical processes. However, this measurement is tedious, imprecise, and time consuming. More generally, industry needs reliable instruments for the thermal characterization of phase change reactors. This paper enables researchers with means and instruments to study the thermal behavior of processes involving the transformation of phase change materials up to 1000 °C. In this work, an original experimental setup is described to analyze the behavior of two high temperature phase change materials: zinc and molten salts. In particular, it is possible to evaluate the 2D solid solidification front evolution with time. The measurements done with zinc show the presence of two thermal regimes. A solidification rate of 20 mm h(-1) is measured with two different approaches: thermocouples and a mechanical probe. Finally, an infrared camera is also used to make the link between the external thermal behavior and the solidification front evolution inside the reactor. When implemented within an inverse numerical method, the use of this instrument as a new external sensor looks promising.

Family therapy training in clinical psychology programs.

In a national questionnaire survey of graduate programs offering the Ph.D. or Psy.D. in clinical psychology, the status of family therapy training was examined. With a 79 per cent response rate (102 programs), the study found that 10 per cent of the nationwide faculty identified themselves as primarily family therapy oriented, 32 per cent of the programs had no family-oriented faculty members, 18 per cent of all psychotherapy courses were family therapy courses, and 21 per cent of the schools had no family therapy course. The ratings of the importance of providing students with family therapy training were found to be unrelated to the number of family therapy courses available but positively correlated with the percentage of family therapy courses within the total curriculum.

Circulating cell wall components derived from gram-negative, not gram-positive, bacteria cause a profound induction of the gene-encoding Toll-like receptor 2 in the CNS.

The recent characterization of human homologs of Toll may be the missing link for the transduction events leading to nuclear factor-kappaB (NF-kappaB) activity and proinflammatory gene transcription during innate immune response. Mammalian cells may express as many as 10 distinct Toll-like receptors (TLRs), although TLR2 is a key receptor for recognizing cell wall components of Gram-positive bacteria. The present study investigated the effects of circulating bacterial cell wall components on the expression of the gene-encoding TLR2 across the mouse brain. Surprisingly, while Gram-negative components caused a robust increase in TLR2 transcription within the cerebral tissue, peptidoglycan (PGN) and lipoteichoic acid (LTA), either alone or combined, failed to modulate the receptor transcript. Indeed, the mRNA levels for TLR2 in the choroid plexus and few other regions of the brain remained similar between vehicle-, LTA-, PGN-, and LTA/PGN-administered mice at all the times evaluated (i.e. 30 min to 24 h post-intraperitoneal injection). This contrasts with the profound de novo expression of TLR2 following a single systemic injection of the lipopolysaccharide (LPS). The signal was first detected in regions devoid of blood-brain barrier and few blood vessels and microcapillaries. A second wave of TLR2 expression was also detected from these structures to their surrounding parenchymal cells that stained for a microglial marker iba1. The rapid induction of IkappaBalpha (index of NF-kappaB activity) and up-regulation of the adaptor protein MyD88 suggest that LPS-induced TLR2 transcription may be dependent on the NF-kappaB pathway. These data provide the evidence that TLR2 is not only present in the brain, but its encoding gene is regulated by cell wall components derived from Gram-negative, not Gram-positive, bacteria. The robust wave of TLR2-expressing microglial cells may have a determinant impact on the innate immune response that occurs in the brain during systemic infection by Gram-negative, not Gram-positive, bacteria.

Low prevalence of neurological and neuropsychological abnormalities in otherwise healthy HIV-1-infected individuals: results from the multicenter AIDS Cohort Study.

Accurate description of the prevalence of neurological impairment in healthy individuals who are infected with human immunodeficiency virus type 1 (HIV-1) has relevance for public health policy, for employment issues, and for planning future health needs. Within the Multicenter AIDS Cohort Study, we determined the cross-sectional prevalence of neurological abnormalities in 270 HIV-1 seropositive homosexual and bisexual men in Centers for Disease Control Groups II and III, using a control group of 193 HIV-1 seronegative homosexual men. Utilizing a neurological and neuropsychological screening battery, we found no differences in the prevalence of neuropsychiatric symptoms or in neuropsychological performance. One hundred nineteen subjects with abnormalities on screening tests completed additional neuropsychological testing and had neurological examinations. The majority had normal results and the frequency of neurological abnormalities and impaired neuropsychological performance was not significantly increased among HIV-1 seropositive subjects. Most of the abnormalities could be attributed to causes other than HIV-1. One subject had mild HIV-1-related dementia, yielding a prevalence of 3.7:1,000 (95% confidence interval: 0.19-23.7:1,000). Magnetic resonance imaging demonstrated sulcal prominence and focal areas of high signal intensity in white matter in 63% of HIV-1 seropositive subjects and 48% of uninfected control subjects. Abnormalities in cerebrospinal fluid were noted in 23 (85%) of 27 HIV-1-infected individuals. Our studies indicate that the prevalence of dementia and other HIV-1-related neurological disorders is very low among healthy HIV-1 seropositive homosexual men. The confounding effects of factors such as substance abuse or preexisting medical conditions must be considered in the neurological evaluation of such patients.