LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice

Angiogenesis plays an important role in tumor growth. Angiogenic growth factors may be useful as biomarkers of antiangiogenic activity since their plasma concentrations correlate with the efficacy of treatments directed toward angiogenic targets. SW2 small-cell lung carcinoma (SCLC), Caki-1 renal cell carcinoma and HCT-116 colon carcinoma tumors produce measurable plasma VEGF, bFGF and TGF in nude mice. Mice bearing these human tumor xenografts were treated orally twice daily with the PKC inhibitor, LY317615 (days 14–30 for SW2 and HCT116, and days 21–39 for Caki-1). Plasma was collected every 3 days from control and treated mice. LY317615 significantly decreased plasma VEGF levels in mice bearing SW2 SCLC and Caki-1 renal cell carcinoma compared to control plasma concentrations beginning 5–7 days after initiating therapy. VEGF plasma levels remained suppressed after termination of LY317615 treatment and for the duration of the study (an additional 2 to 3 weeks). Plasma VEGF levels in mice bearing HCT116 xenografts were not altered by LY317615 treatment and plasma bFGF and TGF- were not altered by LY317615 in any of the animals. As shown by CD31 immunohistochemical staining, LY317615 decreased intratumoral vessel density by nearly 40% in all three tumors. Only the Caki-1 tumor responded to single-agent LY317615 therapy with a measurable tumor growth delay. Thus, unexpectedly inhibition of PKC in vivo led to decreased VEGF production that persisted after therapy as well as to decreased intratumoral vessels. Plasma VEGF was a weak marker of response to LY317615, and plasma bFGF and TGF were not markers of LY317615 activity.Abbreviations bFGF Basic fibroblast growth factor - PKC- Protein kinase C-beta - SCLC Small-cell lung cancer - TGD Tumor growth delay - TGF- Transforming growth factor-beta - VEGF Vascular endothelial growth factor     

Proton and hyperpolarized helium magnetic resonance imaging of radiation-induced lung injury in rats

PURPOSE: To assess the usefulness of hyperpolarized helium (3He) MRI, including apparent diffusion coefficient measurements, in the detection and evaluation of radiation-induced lung injury in rats. METHODS AND MATERIALS: Female Fischer-344 rats were treated to the right lung with fractionated dose of 40 Gy (5 x 8 Gy) using 4-MV photons. Conventional proton (1H) and hyperpolarized (3He) MRI were used to image the lungs 3-6 months after radiation treatment. Apparent diffusion coefficient (ADC) maps of hyperpolarized 3He in the lungs were calculated using a nonlinear, least-squares fitting routine on a pixel-by-pixel basis. After imaging, lungs were processed for histologic assessment of damage. RESULTS: The effect of radiation was time dependent with progressive right lung damage ranging from mild to moderate at 3 months to severe fibrosis with structural deformation at 6 months after radiation. There was a significant decrease in the apparent diffusion coefficient of hyperpolarized 3He gas in radiation-treated lungs. Areas of decreased ADC in the lungs correlated with fibrosis shown by histology. CONCLUSION: This is the first study to show that hyperpolarized 3He MRI can detect radiation-induced lung injury noninvasively. Reduced hyperpolarized 3He ADC values postradiation likely reflect reduced alveolar volumes associated with fibrosis of the interstitium. Future studies at earlier time points may determine whether this noninvasive imaging technique can detect lung damage before clinical symptoms. Development of this new approach of magnetic resonance lung imaging in the rat model of radiation-induced lung injury will increase the ability to develop appropriate algorithms and more accurate models of the normal tissue complication probability.     

Neurosyphilis in newly admitted psychiatric patients: three case reports

BACKGROUND: Neurosyphilis, also known as "general paresis of the insane," at one time accounted for a large portion of admissions to state psychiatric facilities. With the introduction of antibiotics, neurosyphilis is now considered very rare. METHOD: Chart review was performed on patients diagnosed with neurosyphilis who were admitted to a state psychiatric hospital in Raleigh, N.C., during 2002. RESULTS: We identified 3 cases of confirmed neurosyphilis, representing 0.1% of adult admissions, diagnosed in newly admitted psychiatric patients. None of the patients were immunocompromised. Response to antibiotic treatment was poor. CONCLUSIONS: Given the increase in primary and secondary syphilis reported in the 1980s and early 1990s, routine screening of psychiatric patients for the presence of syphilis should be considered.     

Relationships of age at onset with clinical features and cognitive functions in a sample of schizophrenia patients

BACKGROUND: A number of studies investigated the relationships of age at onset with clinical presentation and cognitive performance of schizophrenic patients. The aim of the present study was to assess demographic and clinical characteristics; psychopathologic, social functioning, and quality-of-life ratings; and neuropsychological measures in a sample of patients with stabilized schizophrenia and to identify which factors independently contributed to a multiple regression model with age at onset as the dependent variable. METHOD: Ninety-six consecutive outpatients with schizophrenia (DSM-IV-TR criteria) were included in the study. Assessment instruments were as follows: a semistructured interview, the Clinical Global Impressions scale, the Comprehensive Psychopathological Rating Scale, and the Positive and Negative Syndrome Scale (PANSS) for psycho-pathology of schizophrenia; the Calgary Depression Scale for Schizophrenia (CDSS) for depression; the Social and Occupational Functioning Assessment Scale and the Sheehan Disability Scale for social functioning; the Quality of Life Scale; and a neuro-psychological battery including the Wisconsin Card Sorting Test (WCST) and the Continuous Performance Test. Two models of multiple regression were tested: the first included clinical features and psychopathologic, social functioning, and quality-of-life scales; the second also considered neuro-psychological variables. Data were collected from October 2001 to November 2002. RESULTS: The first multiple regression showed that age at onset was significantly related to scores on the PANSS subscale for negative symptoms (p =.042) and the CDSS (p =.041); the second regression found a relation of age at onset with PANSS score for negative symptoms (p =.002) and 2 neuropsychological measures, number of preservative errors on the WCST and Continuous Performance Test reaction time (p =.0005 for both). CONCLUSION: Our data indicate that, when results of neuropsychological tests are considered, early age at onset of schizophrenia is associated with severity of negative symptoms and compromised cognitive measures of executive functioning and sustained attention.     

Relationships between arteriosclerosis, cerebral amyloid angiopathy and myelin loss from cerebral cortical white matter in Alzheimer's disease

Pathological relationships between damage to the deep white matter of the cerebral cortex [as evidenced by myelin loss (ML)], cerebral amyloid angiopathy (CAA) and arteriosclerosis (ART) were investigated in the brains of 137 patients with autopsy-confirmed Alzheimer's disease (AD), in order to better understand the causes of white matter damage in AD, and the contribution of this to the pathogenesis of the disorder. All 137 patients had some degree of CAA in one or more brain regions although the occipital cortex was severely affected by CAA more frequently, and consequently mean CAA severity score was significantly greater, than other cortical regions. Eighty-seven patients (63.5%) were affected by ML, with more patients showing ML from occipital cortex than from other cortical regions leading to a significantly higher mean ML severity score in this region. One hundred and twenty-six patients (92%) were affected by ART, although the occipital cortex was not more frequently affected by ART than other cortical areas, the mean ART severity score in occipital cortex was nonetheless significantly greater than that of frontal and temporal cortex. Eighty-seven patients showed both CAA and ML, although there was only a weak correlation between degree of CAA and extent of ML (P = 0.035). Forty-seven patients showed ML and significant ART, 16 patients showed significant ART but no ML, 40 patients showed ML in the absence of significant ART and 34 patients showed neither significant ART nor ML. Overall, and for each of the four brain regions, the extent of ML correlated significantly (P < 0.001) with degree of ART. However, when only those 47 patients with ML and significant ART were considered, much stronger correlations between the extent of ML and the degree of ART were achieved both overall and within each of the four brain regions. The overall ART severity score (and overall scores for each pathological marker of ART) significantly correlated with that of CAA (P < 0.001). Pathological processes leading to white matter damage, in terms of ML at least, in AD are thus likely to be heterogeneous. Many patients suffer ML in association with ART, but in others ML cannot be explained by presence of ART or CAA. In such patients, autoregulatory changes in blood vessels might be responsible for ML. The association between the extent of CAA and ART suggests shared risk factors for each pathological change.     

Screening for personality disorder: a comparison of personality disorder assessment by patient and informants

The Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II Version 2.0) is becoming the most favoured instrument to measure personality disorder but takes up to an hour to complete. The Standardized Assessment of Personality (SAP), an informant-based measure, takes 10 to 15 minutes to complete. Both instruments have been validated independently. This study aimed to determine whether the SAP is a suitable screening instrument for personality disorder as measured by the SCID-II. Fifty-seven psychiatric patients were assessed for personality disorder using both the SAP and the SCID-II. The SAP assessments were conducted blind to the results of the SCID-II assessments. Agreement between the two instruments in this population was low (kappa = 0.3). The level of agreement differed between personality disorder categories, ranging from kappa = 0.4 (antisocial) to 0.1 (narcissistic). In this population of patients, the SAP proved to be a poor screen for the SCID-II. The study highlights the discrepancy between informant and self-report assessments for personality disorder.     

Sleep under exposure to high-frequency electromagnetic fields

The controversy about potential health hazards associated with the exposure to electromagnetic fields (EMF) has been recently stimulated by the increasing use of mobile telecommunication devices. Attention has focused here on non-thermal effects of low-level high-frequency radiation, which does not lead to a heating of tissue. Scientific literature on the effects of high-frequency EMFs on sleep is reviewed. The epidemiological studies provide no evidence that sleep disturbances are a relevant complaint under exposure to such fields. Recent sleep laboratory studies have revealed a number of slight effects. Despite their heterogeneity, there seems to be some consistency regarding a slight sleep-promoting effect and an increase of the alpha power of the sleep EEG induced by high-frequency EMFs. However, for both the epidemiological and sleep laboratory studies, the database concerning sleep is up to now very limited. At the present level of knowledge, no final conclusions can be drawn from the available data concerning potential health hazards. Although there seem to be some biological effects, these do not provide evidence for any adverse health consequences. However, further research is needed for a better understanding of the interaction between EMFs and the sleep process.     

α-T-catenin is expressed in human brain and interacts with the Wnt signaling pathway but is not responsible for linkage to chromosome 10 in Alzheimer’s disease

The gene encoding α-T-catenin, CTNNA3, is positioned within a region on chromosome 10, showing strong evidence of linkage to Alzheimer’s disease (AD), and is therefore a good positional candidate gene for this disorder. We have demonstrated that α-T-catenin is expressed in human brain, and like other α-catenins, it inhibits Wnt signaling and is therefore also a functional candidate. We initially genotyped two single-nucleotide polymorphisms (SNPs) in the gene, in four independent samples comprising over 1200 cases and controls but failed to detect an association with either SNP. Similarly, we found no evidence for association between CTNNA3 and AD in a sample of subjects showing linkage to chromosome 10, nor were these SNPs associated with Aβ deposition in brain. To comprehensively screen the gene, we genotyped 30 additional SNPs in a subset of the cases and controls (n>700). None of these SNPs was associated with disease. Although an excellent candidate, we conclude that CTNNA3 is unlikely to account for the AD susceptibility locus on chromosome 10.     

Discussions about cognitive impairment in first medical visits: older patients' perceptions and preferences

Primary care physicians are the first medical contact for most patients with early-stage dementia. However, little is known about older patients' desire for discussions about cognitive problems or the frequency of discussions about cognitive status during primary care visits. To investigate this question, older patients and accompanying individuals were interviewed separately following the first visit with a primary care physician in an outpatient geriatric medical practice. Patients indicated that memory was discussed in 62 percent of visits. When memory was not discussed, almost one-third of patients stated that they would have wanted to discuss it. Physicians were more likely than patients to initiate discussions about memory. Patient factors, including age, gender, the presence of an accompanying individual, number of diagnoses, and the patient's statement that cognitive function was a main goal of the visit, were examined as predictors of the likelihood of discussion of memory during the first visit. Patients who identified discussing cognitive function as a goal of the visit were more likely to have a discussion about memory than those who did not.