GABA and glutamate moderate beta-amyloid related functional connectivity in cognitively unimpaired old-aged adults.

BACKGROUND: Effects of beta-amyloid accumulation on neuronal function precede the clinical manifestation of Alzheimer's disease (AD) by years and affect distinct cognitive brain networks. As previous studies suggest a link between beta-amyloid and dysregulation of excitatory and inhibitory neurotransmitters, we aimed to investigate the impact of GABA and glutamate on beta-amyloid related functional connectivity. METHODS: 29 cognitively unimpaired old-aged adults (age = 70.03 ±â€¯5.77 years) were administered 11C-Pittsburgh Compound B (PiB) positron-emission tomography (PET), and MRI at 7 Tesla (7T) including blood oxygen level dependent (BOLD) functional MRI (fMRI) at rest for measuring static and dynamic functional connectivity. An advanced 7T MR spectroscopic imaging (MRSI) sequence based on the free induction decay acquisition localized by outer volume suppression' (FIDLOVS) technology was used for gray matter specific measures of GABA and glutamate in the posterior cingulate and precuneus (PCP) region. RESULTS: GABA and glutamate MR-spectra indicated significantly higher levels in gray matter than in white matter. A global effect of beta-amyloid on functional connectivity in the frontal, occipital and inferior temporal lobes was observable. Interactive effects of beta-amyloid with gray matter GABA displayed positive PCP connectivity to the frontomedial regions, and the interaction of beta-amyloid with gray matter glutamate indicated positive PCP connectivity to frontal and cerebellar regions. Furthermore, decreased whole-brain but increased fronto-occipital and temporo-parietal dynamic connectivity was found, when GABA interacted with regional beta-amyloid deposits in the amygdala, frontal lobe, hippocampus, insula and striatum. CONCLUSIONS: GABA, and less so glutamate, may moderate beta-amyloid related functional connectivity. Additional research is needed to better characterize their interaction and potential impact on AD.

Controlled release strategy designed for intravitreal protein delivery to the retina.

Therapeutic protein delivery directly to the eye is a promising strategy to treat retinal degeneration; yet, the high risks of local drug overdose and cataracts associated with bolus injection have limited progress, requiring the development of sustained protein delivery strategies. Since the vitreous humor itself is a gel, hydrogel-based release systems are a sensible solution for sustained intravitreal protein delivery. Using ciliary neurotrophic factor (CNTF) as a model protein for ocular treatment, we investigated the use of an intravitreal, affinity-based release system for protein delivery. To sustain CNTF release, we took advantage of the affinity between Src homology 3 (SH3) and its peptide binding partners: CNTF was expressed as a fusion protein with SH3, and a thermogel of hyaluronan and methylcellulose (HAMC) was modified with SH3 binding peptides. Using a mathematical model, the hydrogel composition was successfully designed to release CNTF-SH3 over 7 days. The stability and bioactivity of the released protein were similar to those of commercial CNTF. Intravitreal injections of the bioengineered thermogel showed successful delivery of CNTF-SH3 to the mouse retina, with expected transient downregulation of phototransduction genes (e.g., rhodopsin, S-opsin, M-opsin, Gnat 1 and 2), upregulation of STAT1 and STAT3 expression, and upregulation of STAT3 phosphorylation. This constitutes the first demonstration of intravitreal protein release from a hydrogel. Immunohistochemical analysis of the retinal tissues of injected eyes confirmed the biocompatibility of the delivery vehicle, paving the way towards new intravitreal protein delivery strategies.

Colocalization of cerebral iron with Amyloid beta in Mild Cognitive Impairment.

Quantitative Susceptibility Mapping (QSM) MRI at 7 Tesla and 11-Carbon Pittsburgh-Compound-B PET were used for investigating the relationship between brain iron and Amyloid beta (Aß) plaque-load in a context of increased risk for Alzheimer's disease (AD), as reflected by the Apolipoprotein E ε4 (APOE-e4) allele and mild cognitive impairment (MCI) in elderly subjects. Carriers of APOE-e4 with normal cognition had higher cortical Aß-plaque-load than non-carriers. In MCI an association between APOE-e4 and higher Aß-plaque-load was observable both for cortical and subcortical brain-regions. APOE-e4 and MCI was also associated with higher cortical iron. Moreover, cerebral iron significantly affected functional coupling, and was furthermore associated with increased Aß-plaque-load (R2-adjusted = 0.80, p < 0.001) and APOE-e4 carrier status (p < 0.001) in MCI. This study confirms earlier reports on an association between increased brain iron-burden and risk for neurocognitive dysfunction due to AD, and indicates that disease-progression is conferred by spatial colocalization of brain iron deposits with Aß-plaques.

Differentiation of Metastatic and Non-Metastatic Mesenteric Lymph Nodes by Strain Elastography in Surgical Specimens.

PURPOSE: To investigate if strain elastography could differentiate between metastatic and non-metastatic mesenteric lymph nodes ex-vivo. MATERIALS AND METHODS: 90 mesenteric lymph nodes were examined shortly after resection from 25 patients including 17 patients with colorectal cancer and 8 patients with Crohn's disease. Ultrasound-based strain elastography was performed with a linear probe. Tissue hardness in lymph nodes was assessed using visual scales and measuring the strain ratio. B-mode characteristics were also recorded. Pathological diagnosis with grading of fibrosis served as the reference standard. RESULTS: 20 lymph nodes were metastatic and 70 lymph nodes were non-metastatic. The strain ratios of metastatic and non-metastatic lymph nodes were significantly different (1.83 vs. 1.42, p = 0.021). The VAS scale (0 - 100) for tissue hardness gave higher mean values for metastatic than non-metastatic nodes, but the difference was not significant (65.5 vs. 55.0, p = 0.055). There was no difference between lymph nodes in Crohn's and non-metastatic cancer specimens. The metastatic lymph nodes were significantly more fibrotic than the non-metastatic lymph nodes by the ordinal fibrosis score (0 - 3). In an ROC analysis, quantitative strain imaging was not superior to the measurement of the short-axis diameter of lymph nodes in differentiating metastatic from non-metastatic mesenteric lymph nodes ex-vivo. CONCLUSION: Strain elastography is correlated to fibrosis in lymph nodes and a significant difference was observed on a group level using the strain ratio. Due to measurement overlap, individual mesenteric lymph nodes could not be identified accurately as metastatic or not in this ex-vivo model by strain imaging alone.

Polyvinylpyrrolidone induced artefactual prolongation of activated partial thromboplastin times in intravenous drug users with renal failure.

Essentials Prolonged activated partial thromboplastin times (APTT) were found in drug users with renal failure. An oral methadone solution containing polyvinylpyrrolidone (PVP) had been injected intravenously. Spiking normal plasma with increasing concentrations of PVP resulted in artifically prolonged APTT. APTT prolongation may indicate PVP deposits as underlying cause in patients with renal failure. SUMMARY: Unexpectedly prolonged activated partial thromboplastin times (APTTs) were noted in several patients with chronic renal insufficiency and a history of intravenous drug abuse. Deposits of polyvinylpyrrolidone (PVP), an excipient in one oral methadone solution used in opioid maintenance programs, were found in renal biopsies. One case is described in detail, and this is followed by a summary of findings in 11 other patients and the results of an in vitro experiment in which plasma was spiked with PVP at increasing concentrations. APTTs measured with STA PTT automate (Stago) were prolonged in all patients and in spiked samples, whereas supplemental coagulation parameters and APTTs measured with HemosIL SynthAsil or Actin FSL (Siemens) were within reference intervals. These results indicate that interference with APTTs by PVP is reagent-dependent. We suggest that a prolonged APTT should raise the suspicion of PVP deposit-associated kidney disease in patients with chronic renal failure and a history of intravenous drug abuse.

Strain Elastography Evaluation of Rectal Tumors: Inter- and Intraobserver Reproducibility.

PURPOSE: Elastography is a promising method for the identification and differentiation of malignant tissue in several organ systems. The primary aim was to evaluate the inter- and intraobserver reproducibility of endorectal strain elastography differentiation of adenomas and adenocarcinomas. The secondary aim was to compare the performance of strain elastography to endorectal ultrasonography (ERUS) examinations. MATERIALS AND METHODS: Consecutive inclusion of 95 ERUS examinations and 110 elastography video loops with ERUS overlay mode. Video loops were randomized and evaluated by eight observers on two separate occasions. Observers were blinded to all clinical information except the circumferential location of the tumor. A continuous visual analog scale (VAS) and a categorical scale (W-score) were used for elastography evaluation. ERUS loops were T-staged according to the TNM classification system. Histopathological evaluation of surgical resection specimen was used as the reference standard. RESULTS: Strain elastography visual evaluation yielded intraobserver variability from 0.86 to 0.97 and interobserver variability of 0.99. VAS strain elastography differentiation of adenomas (pT0) and adenocarcinomas (pT1 - 4) yielded sensitivity, specificity, accuracy, positive and negative predictive values of 0.94, 0.71, 0.89, 0.92 and 0.78, respectively. The corresponding ERUS values were 0.83, 0.64, 0.79, 0.88 and 0.54, respectively. CONCLUSION: Visual evaluation of elastography loops is highly reproducible in an offline setting with blinded observers, and correlates significantly with pT-stages. Strain elastography performs better than ERUS and might consequently improve staging.

Endorectal ultrasonography, strain elastography and MRI differentiation of rectal adenomas and adenocarcinomas.

AIM: Strain elastography is a method for recording tissue hardness. Strain in different areas may be compared using strain ratio (SR). The aims of this study were to validate a previously proposed SR cut-off value of 1.25 for differentiating adenocarcinomas from adenomas and to compare the performance of endorectal ultrasonography (ERUS), strain elastography and MRI in the same patients. METHOD: A prospective evaluation of 120 consecutive patients with rectal neoplasia, using a predetermined elastography strain ratio cut-off value, was performed to differentiate adenomas from adenocarcinomas. ERUS and MRI were performed according to standard routine at Haukeland University Hospital, defining T0 as adenomas and T1-T4 as adenocarcinomas. Subsequent histopathology was used as the reference standard. RESULTS: Histopathological evaluation revealed 21 adenomas and 99 adenocarcinomas. Sensitivity, specificity and accuracy (with 95% CI) were as follows: ERUS: 0.96 (0.90-0.99), 0.62 (0.40-0.80) and 0.90 (0.83-0.94); elastography SR: 0.96 (0.90-0.99), 0.86 (0.66-0.96) and 0.94 (0.88-0.97); and MRI: 0.99 (0.94-1.00), 0.07 (0.00-0.31) and 0.87 (0.80-0.93). CONCLUSION: This study confirms that the elastography SR assessment accurately differentiates sessile adenomas from adenocarcinomas. SR assessment has a superior ability to differentiate adenomas and adenocarcinomas when compared with ERUS and MRI. MRI examination seems unable to recognize adenomas and should be interpreted with care when early-stage rectal neoplasia is suspected.

Combined endorectal ultrasonography and strain elastography for the staging of early rectal cancer.

AIM: Strain elastography is a novel approach to rectal tumour evaluation. The primary aim of this study was to correlate elastography to pT stages of rectal tumours and to assess the ability of the method to differentiate rectal adenomas (pT0) from early rectal cancer (pT1-2). Secondary aims were to compare elastography with endorectal ultrasonography (ERUS) and to propose a combined strain elastography and ERUS staging algorithm. METHOD: In all, 120 consecutive patients with a suspected rectal tumour were examined in this staging study. Patients receiving surgery without neoadjuvant radiotherapy were included (n = 59). All patients were examined with ERUS and elastography. Treatment decisions were made by multidisciplinary team (MDT) assessment, without considering the strain elastography examination. RESULTS: Histopathology identified 21 adenomas, 13 pT1, 9 pT2, 15 pT3 and one pT4. Mean elastography strain ratios were predictive of T stage (P = 0.01). Differentiation of adenomas from early rectal cancer (pT1-2) had sensitivity, specificity and accuracy of 0.82, 0.86 and 0.84 for elastography and 0.82, 0.62 and 0.72 for ERUS. A combined staging algorithm was developed to identify tumours eligible for local resection. Based on MDT evaluation 32% of tumours later identified as pT0 or pT1 were treated with total mesorectal excision, even though a local excision might have sufficed. Combined ERUS and elastography evaluation would have significantly reduced this number to 9% (P = 0.008). CONCLUSION: Elastography may improve the staging of adenomas and early rectal cancer compared with ERUS alone. Combined ERUS and elastography assessment is likely to further improve the selection of patients for local resection.

Strain assessment in surgically resected inflammatory and neoplastic bowel lesions.

PURPOSE: To investigate whether ultrasound-based strain imaging can discriminate between colorectal adenocarcinomas and stenotic Crohn's lesions in newly resected surgical specimens. MATERIALS AND METHODS: Resected surgical specimens from 27 patients electively operated for colorectal tumors or stenotic lesions from Crohn's disease were prospectively examined with ultrasonography using a Hitachi HV 900 US scanner with real-time elastography (RTE). Three different methods were applied to assess tissue strain: A four-level categorical visual classification, a continuous visual analog scale (VAS, 0 - 100) and a strain ratio (SR) measurement between the lesion and surrounding reference tissue. The imaged sections were marked and subsequently examined by a pathologist. Results from RTE were evaluated according to diagnosis, degree of fibrosis, inflammatory parameters, tumor stage and grade. RESULTS: 16 sections from Crohn's lesions, 18 sections from adenocarcinomas and 4 sections from adenomas were examined. Both adenocarcinomas and Crohn's lesions were found to be harder than the surrounding tissue, but they could not be discriminated from each other by any of the strain imaging evaluation methods. All adenocarcinomas had significantly higher strain ratios than adenomas. The categorical classification differentiated poorly between Crohn's lesions, adenocarcinomas and adenomas. Categorical evaluation and VAS score showed fair interobserver agreement. SR measurements provided semi-quantitative strain data and added improved information about elasticity properties, despite substantial intra-observer variation. CONCLUSION: Sonoelastography with SR measurements and visual evaluation of strain differences could not differentiate stenotic Crohn's lesions from adenocarcinomas in resected bowel specimens. A small number of adenomas were found to be significantly softer than adenocarcinomas using the same evaluation methods. The tumor stage or grade did not have a significant impact on the elastography results.

Expression of cyclin D1a and D1b as predictive factors for treatment response in colorectal cancer.

BACKGROUND: The aim of this study was to investigate the value of the cyclin D1 isoforms D1a and D1b as prognostic factors and their relevance as predictors of response to adjuvant chemotherapy with 5-fluorouracil and levamisole (5-FU/LEV) in colorectal cancer (CRC). METHODS: Protein expression of nuclear cyclin D1a and D1b was assessed by immunohistochemistry in 335 CRC patients treated with surgery alone or with adjuvant therapy using 5-FU/LEV. The prognostic and predictive value of these two molecular markers and clinicopathological factors were evaluated statistically in univariate and multivariate survival analyses. RESULTS: Neither cyclin D1a nor D1b showed any prognostic value in CRC or colon cancer patients. However, high cyclin D1a predicted benefit from adjuvant therapy measured in 5-year relapse-free survival (RFS) and CRC-specific survival (CSS) compared to surgery alone in colon cancer (P=0.012 and P=0.038, respectively) and especially in colon cancer stage III patients (P=0.005 and P=0.019, respectively) in univariate analyses. An interaction between treatment group and cyclin D1a could be shown for RFS (P=0.004) and CSS (P=0.025) in multivariate analysis. CONCLUSION: Our study identifies high cyclin D1a protein expression as a positive predictive factor for the benefit of adjuvant 5-FU/LEV treatment in colon cancer, particularly in stage III colon cancer.

Endorectal elastography in the evaluation of rectal tumours.

AIM: Real-time elastography visualizes tissue compliance using an ultrasound platform. Elastography has been used, particularly in the breast, to characterize indeterminate lesions on B-mode imaging as either benign or malignant. The primary aim of this study was to assess the feasibility of routine endorectal elastography to evaluate rectal neoplasia. The secondary aim was to correlate elastography data with histopathological end-points. METHOD: Sixty-nine patients referred to the outpatient clinic of the Department of Colorectal Surgery at Haukeland University Hospital for the evaluation of rectal tumours were included in this prospective cohort study. All patients underwent digital rectal examination, rigid rectoscopy with biopsy, endorectal ultrasonography and endorectal elastography. In each case a strain ratio was calculated, comparing the tumour tissue with adjacent reference tissue that appeared normal on ultrasound scanning. RESULTS: Histopathologically there were 23 adenomas and 45 adenocarcinomas. One patient died before surgical treatment. Adequate elastography images were obtained in 66/69 (96%) patients. Optimal discrimination of malignant and benign lesions was obtained using a strain ratio cut-off value of 1.25 (sensitivity, 0.93; specificity, 0.96; and accuracy, 0.94). CONCLUSION: Endorectal elastography can be performed as an integral part of the clinical evaluation of rectal tumours and has good patient compliance. The method is a promising modality for the discrimination between adenocarcinoma and adenoma of the rectum.

Interstitial nephritis, acute renal failure in a patient with non-fulminant hepatitis A infection.

This is the first report from Norway of a patient with interstitial nephritis and renal failure due to non-fulminant hepatitis A virus (HAV) infection. HAV infection was confirmed by positive anti-HAV IgM serology. All tests for other virus infections were negative. At admittance serum creatinine (s-Creat) and blood urea nitrogen (BUN) concentration were 539 microlmol/l and 32.6 mmol/l increasing the following days to 890 micromol/l and 39.9 mmol/l, respectively. Nine courses of hemodialysis had to be given. Kidney biopsy specimen showed interstitial edema, lymphocytic cell infiltration and acute tubular injury with normal glomeruli. Examination with immunohistochemistry was negative. In contrast to the findings associated with HBV and HCV infection in which glomerular disease is predominantly found, the HAV infection in our patient was associated with interstitial nephritis and acute tubular necrosis. The prognosis of the renal failure due to HAV infection was good although the recovery was substantially delayed.

HIV infection in U.S. correctional systems: its effect on the community.

Increased rates of HIV infection and risk-taking behaviors among incarcerated men and women make the fight against HIV within the prison and jail systems an especially critical issue in community health. Overcrowded conditions impact on the rotation of inmates in and out of the correctional system. This revolving door phenomenon has implications for disease prevention and control within the community into which the inmates are released. As more people pass in and out of jails and prisons, more problems and diseases associated with incarceration pass into the community. The special needs of the prison population must be taken into consideration not only by nurses but also by all health care workers and correctional officials when planning and implementing control and prevention strategies.