Opioid Avoidance in Liver Transplant Recipients: Reduction in Postoperative Opioid Use Through a Multidisciplinary Multimodal Approach.

The prevalence of substance use disorder in the liver transplantation (LT) population makes postoperative pain management challenging. We report our initial experience with a novel, comprehensive, multidisciplinary opioid avoidance pathway in 13 LT recipients between January 2018 and September 2019. Patients received comprehensive pre-LT education on postoperative opioid avoidance by the surgeon, pharmacist, and psychologist at the time of listing. Immediately after LT, patients received a continuous incisional ropivacaine infusion, ketamine, acetaminophen, and gabapentin as standard nonopioid medications; rescue opioids were used as needed. We compared outcomes with a historical cohort of 27 LT recipients transplanted between August 2016 and January 2018 managed primarily with opioids. On average, opioid avoidance patients used 92% fewer median (interquartile range [IQR]) morphine milligram equivalents (MMEs) versus the historical cohort (7 [1-11] versus 87 [60-130] MME; P < 0.001) per postoperative day over a similar length of stay (8 [7-10] versus 6 [6-10] days; P = 0.14). Fewer outpatient MMEs were prescribed within the first 60 days after LT in the opioid avoidance group versus the historical cohort: 125 (25-150) versus 270 (0-463) MME (P = 0.05). This proof-of-concept study outlines the potential to profoundly reduce opioid utilization in the LT population using a comprehensive multidisciplinary approach.

Aggressive Epstein-Barr virus-negative B-cell post-transplant lymphoproliferative disorder in a hepatitis C-negative liver transplant recipient who received a hepatitis C-positive graft: Implications for D+/R- hepatitis C virus seroconversion.

Post-transplant lymphoproliferative disorder (PTLD) is an uncommon, but well-described complication after liver transplantation. Most recently, Hepatitis C virus (HCV) has been implicated in the development of PTLD. A HCV-negative 62-year-old man with autoimmune hepatitis received a HCV nucleic acid amplification test-positive liver graft from a 73-year-old brain-dead donor (D+/R-). After his recovery from the operation, the patient was treated for HCV and achieved an undetectable viral load. He was readmitted 6 months after transplant with a spontaneous perisplenic hematoma, weight loss, failure to thrive, low-grade fevers, and abnormal liver function tests. He had a rapid clinical deterioration and expired shortly after admission. His liver biopsy demonstrated EBV-negative monomorphic B-cell PTLD. Our case is the first to report an aggressive early-onset EBV-negative monomorphic B-cell PTLD in a HCV D+/R- liver transplant. This case illustrates the paucity of knowledge on HCV seroconversion and its involvement in EBV-negative monomorphic B-cell PTLD development.

Visually Evoked 3-5 Hz Membrane Potential Oscillations Reduce the Responsiveness of Visual Cortex Neurons in Awake Behaving Mice.

Low-frequency membrane potential (Vm) oscillations were once thought to only occur in sleeping and anesthetized states. Recently, low-frequency Vm oscillations have been described in inactive awake animals, but it is unclear whether they shape sensory processing in neurons and whether they occur during active awake behavioral states. To answer these questions, we performed two-photon guided whole-cell Vm recordings from primary visual cortex layer 2/3 excitatory and inhibitory neurons in awake mice during passive visual stimulation and performance of visual and auditory discrimination tasks. We recorded stereotyped 3-5 Hz Vm oscillations where the Vm baseline hyperpolarized as the Vm underwent high amplitude rhythmic fluctuations lasting 1-2 s in duration. When 3-5 Hz Vm oscillations coincided with visual cues, excitatory neuron responses to preferred cues were significantly reduced. Despite this disruption to sensory processing, visual cues were critical for evoking 3-5 Hz Vm oscillations when animals performed discrimination tasks and passively viewed drifting grating stimuli. Using pupillometry and animal locomotive speed as indicators of arousal, we found that 3-5 Hz oscillations were not restricted to unaroused states and that they occurred equally in aroused and unaroused states. Therefore, low-frequency Vm oscillations play a role in shaping sensory processing in visual cortical neurons, even during active wakefulness and decision making.SIGNIFICANCE STATEMENT A neuron's membrane potential (Vm) strongly shapes how information is processed in sensory cortices of awake animals. Yet, very little is known about how low-frequency Vm oscillations influence sensory processing and whether they occur in aroused awake animals. By performing two-photon guided whole-cell recordings from layer 2/3 excitatory and inhibitory neurons in the visual cortex of awake behaving animals, we found visually evoked stereotyped 3-5 Hz Vm oscillations that disrupt excitatory responsiveness to visual stimuli. Moreover, these oscillations occurred when animals were in high and low arousal states as measured by animal speed and pupillometry. These findings show, for the first time, that low-frequency Vm oscillations can significantly modulate sensory signal processing, even in awake active animals.

Disparities in Liver Transplantation for Nonalcoholic Steatohepatitis in Women.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is the fastest-growing indication for liver transplantation (LT). Sex disparities among patients with cirrhosis on the LT waitlist are well known. We wanted to understand these disparities further in women with end-stage liver disease patients listed for NASH cirrhosis in a contemporary cohort. METHODS: We used data from the Scientific Registry of Transplant Recipients to assess sex racial, and ethnic differences in NASH patients listed for LT. Adults transplanted from August 1997 to June 2021 were included. Inferential statistics were used to evaluate differences with univariate and multivariate comparisons, including competitive risk analysis. RESULTS: During the study time period, we evaluated 12 844 LT for NASH cirrhosis. Women were transplanted at a lower rate (46.5% versus 53.5%; P  < 0.001) and higher model for end-stage liver disease (MELD) (23.8 versus 22.6; P < 0.001) than men. Non-White women were transplanted at a higher MELD (26.1 versus 23.1; P  < 0.001) than White women and non-White male patients (26.1 versus 24.8; P  < 0.001). Graft and patient survivals were significantly different ( P  < 0.001) between non-White women and White women and men (White and non-White). CONCLUSIONS: Evaluation of LT candidates in the United States demonstrates women with NASH cirrhosis have a higher MELD than men at LT. Additional disparities exist among non-White women with NASH as they have higher MELD and creatinine at LT compared with White women. After LT, non-White women have worse graft and patient survival compared with men or White women. These data indicate that non-White women with NASH are the most vulnerable on the LT waitlist.

Shifts in attention drive context-dependent subspace encoding in anterior cingulate cortex in mice during decision making.

Attention supports decision making by selecting the features that are relevant for decisions. Selective enhancement of the relevant features and inhibition of distractors has been proposed as potential neural mechanisms driving this selection process. Yet, how attention operates when relevance cannot be directly determined, and the attention signal needs to be internally constructed is less understood. Here we recorded from populations of neurons in the anterior cingulate cortex (ACC) of mice in an attention-shifting task where relevance of stimulus modalities changed across blocks of trials. In contrast with V1 recordings, decoding of the irrelevant modality gradually declined in ACC after an initial transient. Our analytical proof and a recurrent neural network model of the task revealed mutually inhibiting connections that produced context-gated suppression as observed in mice. Using this RNN model we predicted a correlation between contextual modulation of individual neurons and their stimulus drive, which we confirmed in ACC but not in V1.

Shifts in attention drive context-dependent subspace encoding in anterior cingulate cortex during decision making.

Attention is a cognitive faculty that selects part of a larger set of percepts, driven by cues such as stimulus saliency, internal goals or priors. The enhancement of the attended representation and inhibition of distractors have been proposed as potential neural mechanisms driving this selection process. Yet, how attention operates when the cue has to be internally constructed from conflicting stimuli, decision rules, and reward contingencies, is less understood. Here we recorded from populations of neurons in the anterior cingulate cortex (ACC), an area implicated in ongoing error monitoring and correction during decision conflicts, in a challenging attention-shifting task. In this task, mice had to attend to the rewarded modality when presented identical auditory and visual stimuli in two contexts without direct external cues. In the ACC, the irrelevant stimulus continuously became less decodable than the relevant stimulus as the trial progressed to the decision point. This contrasted strongly with our previous findings in V1 where both relevant and irrelevant stimuli were equally decodable throughout the trial. Using analytical tools and a recurrent neural network (RNN) model, we found that the linearly independent representation of stimulus modalities in ACC was well suited to context-gated suppression of a stimulus modality. We demonstrated that the feedback structure of lateral connections in the RNN consisted of excitatory interactions between cell ensembles representing the same modality and mutual inhibition between cell ensembles representing distinct stimulus modalities. Using this RNN model showing signatures of context-gated suppression, we predicted that the level of contextual modulation of individual neurons should be correlated with their relative responsiveness to the two stimulus modalities used in the task. We verified this prediction in recordings from ACC neurons but not from recordings from V1 neurons. Therefore, ACC effectively operates on low-dimensional neuronal subspaces to combine stimulus related information with internal cues to drive actions under conflict.

Continuous multiplexed population representations of task context in the mouse primary visual cortex.

Effective task execution requires the representation of multiple task-related variables that determine how stimuli lead to correct responses. Even the primary visual cortex (V1) represents other task-related variables such as expectations, choice, and context. However, it is unclear how V1 can flexibly accommodate these variables without interfering with visual representations. We trained mice on a context-switching cross-modal decision task, where performance depends on inferring task context. We found that the context signal that emerged in V1 was behaviorally relevant as it strongly covaried with performance, independent from movement. Importantly, this signal was integrated into V1 representation by multiplexing visual and context signals into orthogonal subspaces. In addition, auditory and choice signals were also multiplexed as these signals were orthogonal to the context representation. Thus, multiplexing allows V1 to integrate visual inputs with other sensory modalities and cognitive variables to avoid interference with the visual representation while ensuring the maintenance of task-relevant variables.

Non-Lung Solid Organ Transplantation From SARS-CoV-2-Positive Donors to Uninfected Recipients.

BACKGROUND: There is a paucity of evidence on the risk of donor-recipient transmission of the SARS-CoV-2 in solid organ transplant recipients. Initial impressions suggest non-lung solid organs may be safely transplanted from SARS-CoV-2-positive donors without risk of viral transmission. METHODS: We reviewed clinical results of transplants in which SARS-CoV-2-negative recipients received non-lung solid organs from SARS-CoV-2-positive donors at a single transplant center. No prisoners were used in this study, and participants were neither coerced nor paid. The manuscript was created in compliance with the Helsinki Congress and the Declaration of Istanbul. RESULTS: Between June 2021 and January 2023, we transplanted 26 solid organs, including 13 kidneys, 8 livers, 3 hearts, and 1 simultaneous heart and kidney, from 23 SARS-CoV-2-positive donors into 25 SARS-CoV-2 negative recipients. Two of the recipients had a positive SARS-CoV-2 real-time polymerase chain reaction after transplantation, but otherwise, patients had no SARS-CoV-2-related complications, and all patients to date are alive with excellent allograft function. CONCLUSION: Transplantation of non-lung solid organs from SARS-CoV-2-positive donors into uninfected recipients can be safely performed without adverse effects from SARS-CoV-2.

High mortality of cocaine-related ischemic colitis: a hybrid cohort/case-control study.

BACKGROUND: Isolated case reports describe bowel ischemia in cocaine users, and the optimal management of these patients remains uncertain. DESIGN: Case-control study. SETTING: Teaching hospitals. PATIENTS: Patients hospitalized for colonic ischemia related to cocaine compared with noncocaine-related ischemic colitis. Cases were identified by using ICD-9 codes and laboratory urine toxicology tests. Patients were included if they had a confirmed diagnosis of bowel ischemia by CT, colonoscopy, angiography, or, in the case of emergency exploration, a pathology report showing bowel ischemia and a urine toxicology test that was positive for cocaine. Controls were individuals who met the same criteria but had no history of cocaine use and a urine test negative for cocaine. Charts were individually audited for accuracy of coding. MAIN OUTCOME MEASUREMENTS: Mortality and its risk factors. RESULTS: Patients with cocaine-related ischemia were significantly younger and had a significantly (P < .05) higher mortality rate than patients with ischemic colitis unrelated to cocaine (cocaine: 5/19 [26%] and noncocaine: 6/78 [7.7%]). The cause of death in all cases was septic shock caused by extensive bowel ischemia. Multivariate logistic regression analysis showed that cocaine-related ischemic colitis was a significant risk factor for mortality (odds ratio 5.77; 95% CI, 1.37-24.39) as was the need for surgical intervention (odds ratio 4.95; 95% CI, 1.22-20.12). LIMITATIONS: Retrospective design. CONCLUSIONS: Cocaine-related ischemic colitis has a high mortality. In young patients presenting with acute abdominal pain and/or rectal bleeding with evidence of bowel wall thickening or pneumatosis on imaging studies or colonoscopy, cocaine-related ischemia should be considered. Testing for cocaine use may help identify patients at high risk of sepsis and death.

Endoscopic ultrasound fine-needle aspiration characteristics of primary adenocarcinoma versus other malignant neoplasms of the pancreas.

BACKGROUND: Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) is often used to assist in the evaluation of pancreatic lesions and may help to diagnose benign versus malignant neoplasms. However, there is a paucity of literature regarding comparative EUS characteristics of various malignant pancreatic neoplasms (primary and metastatic). OBJECTIVE: To compare and characterize primary pancreatic adenocarcinoma versus other malignant neoplasms, hereafter referred to as nonprimary pancreatic adenocarcinoma (NPPA), diagnosed by EUS-guided FNA. METHODS: The present study was a retrospective analysis of a prospectively maintained database. The setting was a tertiary care, academic medical centre. Patients referred for suspected pancreatic neoplasms were evaluated. Based on EUS-FNA characteristics, primary pancreatic adenocarcinoma was differentiated from other malignant neoplasms. The subset of other neoplasms was defined as malignant lesions that were 'NPPAs' (ie, predominantly solid or solid/cystic based on EUS appearance and primary malignant lesions or metastatic lesions to the pancreas). Pancreatic masses that were benign cystic lesions (pseudocyst, simple cyst, serous cystadenoma) and focal inflammatory lesions (acute, chronic and autoimmune pancreatitis) were excluded. RESULTS: A total of 230 patients were evaluated using EUS-FNA for suspected pancreatic mass lesions. Thirty-eight patients were excluded because they were diagnosed with inflammatory lesions or had purely benign cysts. One hundred ninety-two patients had confirmed malignant pancreatic neoplasms (ie, pancreatic adenocarcinoma [n=144], NPPA [n=48]). When comparing adenocarcinoma with NPPA lesions, there was no significant difference in mean age (P=0.0675), sex (P=0.3595) or average lesion size (P=0.3801). On average, four FNA passes were necessary to establish a cytological diagnosis in both lesion subtypes (P=0.396). Adenocarcinomas were more likely to be located in the pancreatic head (P=0.0198), whereas masses in the tail were more likely to be NPPAs (P=0.0006). Adenocarcinomas were also more likely to exhibit vascular invasion (OR 4.37; P=0.0011), malignant lymphadenopathy (P=0.0006), pancreatic duct dilation (OR 2.4; P=0.022) and common bile duct dilation (OR 2.87; P=0.039). CONCLUSIONS: Adenocarcinoma was more likely to be present in the head of the pancreas, have lymph node and vascular involvement, as well as evidence of pancreatic duct and common bile duct obstruction. Of all malignant pancreatic lesions analyzed by EUS-FNA, 25% were NPPA, suggesting that FNA is crucial in establishing a diagnosis and may be helpful in preoperative planning.

Short- and Long-Term Outcomes for Ethnic Minorities in the United States After Liver Transplantation: Parsing the Hispanic Paradox.

BACKGROUND: Racial and ethnic minorities are disproportionally affected by end-stage liver disease. Unfortunately, disparities in referrals to liver transplantation (LT), organ allocation, and posttransplant outcomes exist in this population. METHODS: We performed a retrospective analysis of patients over the age of 18 years undergoing LT in the United States using the Scientific Registry of Transplant Recipients from 2002 to 2016. We evaluated factors associated with patient and graft outcomes and explored the effect of race and ethnicity along with social variables. RESULTS: During the study time period, 78,999 patients received LT. Of these, 60,102 were non-Hispanic White (NHW), 7988 were African American (AA), and 10,909 were Hispanic. AA had significantly lower patient survival, graft survival, and death-censored graft survival at both 1 and 5 years when compared to NHW. Conversely, at 1 and 5 years, patient survival and graft survival were significantly higher for Hispanics compared to NWH. In addition, AA had significantly lower survival outcomes compared to Hispanics. On multivariate analysis after controlling for race/ethnicity, age, AA race, diagnosis, and deceased donor were independent risk factors for patient death and graft failure. CONCLUSIONS: Despite socioeconomic disadvantages seen among Hispanics, this population appears to have improved short- and long-term survival after LT compared to NHW and AA.

Drug and herbal/dietary supplements-induced liver injury: A tertiary care center experience.

BACKGROUND: Drug-induced liver injury (DILI) and herbal/dietary supplements (HDS) related liver injury present unique diagnostic challenges. Collaboration between the clinician and the pathologist is required for an accurate diagnosis and management. AIM: To report our experience on the clinical-pathological findings of hepatic injury caused by drugs/HDS. METHODS: A retrospective review of clinically proven cases of DILI/HDS who presented to our institution from January 1, 2013 to December 31, 2017 was performed. Slides were reviewed for histopathological patterns of injury and correlated with the causative agent. Out of 600 patients presenting with unexplained rise in liver enzymes undergoing biopsy, 107 were suspected to have DILI/HDS. Of these, 53 had a directly linked exposure to drug/herbal supplements. Fifteen patients were excluded for concurrent known liver disease. Thirty-eight patients with clinically proven DILI/HDS were finally included. RESULTS: Thirty-eight cases of DILI/HDS with a male:female of 1:1.5 and mean age of 51 ± 3 years were identified. DILI was identified in 84.2% cases while HDS injury in 15.8%. Acute hepatitis (42.1%) was the most common pattern of injury while granulomatous hepatitis (2.6%) was the least common. We found one case of acute-cholestasis due to rivaroxaban and two cases of cholestatic-hepatitis due to rizatriptan and trimethobenzamide-hydrochloride that, to the best of our knowledge, have not been previously reported. One case of steatohepatitis due to trimethoprim-sulfamethoxazole and three unusual cases of cholestatic-hepatitis with bile duct injury and steatosis due to dronedarone, C4-Extreme and hydroxycut, were also seen. Of our cohort, 81.6% of the patients fared well with discontinuation of drug and 18.4% underwent transplant; of which 42.9% were deceased. CONCLUSION: We describe the clinical findings, histopathological patterns of injury and clinical outcomes caused by drugs. In particular, we report a few previously unreported/ rarely observed clinical and histopathological patterns of hepatic injury.

Combination treatment with octreotide, midodrine, and albumin improves survival in patients with type 1 and type 2 hepatorenal syndrome.

INTRODUCTION: Few therapeutic modalities exist for the treatment of hepatorenal syndrome (HRS). The combination of octreotide, midodrine, and albumin has shown possible benefit in small preliminary studies in improving renal function and short-term survival. METHODS: We examined the effect of octreotide, midodrine, and albumin on survival (censored for liver transplantation) and renal function in patients with HRS type 1 and type 2, compared with a historical cohort that did not receive this therapy (control group). RESULTS: Seventy-five patients with HRS received octreotide, midodrine, and albumin and 87 did not constitute the control group. HRS type 1 was present in 102 individuals and HRS type 2 in 60. Transplantation was performed in 45% of patients in the treatment group as compared with 26% of patients in the control group although a significant difference in transplantation rate was seen in only HRS type 2. In the treatment arm, transplant-free survival was higher compared with the control arm (median survival 101 d vs. 18 d, P<0.0001). Survival was significantly better in the treatment arm in both HRS type 1 (P=0.0003) and HRS type 2 (P=0.009). In multivariable analysis, treatment with octreotide, midodrine, and albumin (P=0.0001) and HRS type 2 (P=0.05) were independently associated with improved survival. Renal function was significantly improved at 1 month (glomerular filtration rate 48 mL/min) in the treatment group compared with the control group (34 mL/min), P=0.03. CONCLUSIONS: The therapeutic regimen of octreotide, midodrine, and albumin significantly improved short-term survival and renal function in both HRS type 1 and type 2. This may provide a significant benefit as a bridge to liver transplantation in HRS type 1 and may prevent progression of HRS type 2 to HRS type 1.

Predictors of malignancy and recommended follow-up in patients with negative endoscopic ultrasound-guided fine-needle aspiration of suspected pancreatic lesions.

BACKGROUND: Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) can characterize and diagnose pancreatic lesions as malignant, but cannot definitively rule out the presence of malignancy. Outcome data regarding the length of follow-up in patients with negative or nondiagnostic EUS-FNA of pancreatic lesions are not well-established. OBJECTIVE: To determine the long-term outcome and provide follow-up guidance for patients with negative EUS-FNA diagnosis of suspected pancreatic lesions based on imaging predictors. METHODS: A retrospective review of patients undergoing EUS-FNA for suspected pancreatic lesions, but with negative or nondiagnostic FNA results was conducted at a tertiary care referral medical centre. Patient demographics, EUS imaging characteristics and follow-up data were examined. RESULTS: Seventeen of 55 patients (30.9%) with negative/nondiagnostic FNA were subsequently diagnosed with pancreatic malignancy. The risk of cancer was significantly higher for patients who had associated lymph nodes on EUS (P<0.001) and vascular involvement on EUS (P=0.001). The mean time to diagnosis in the group with falsenegative EUS-FNA diagnosis was 66 days. The true-negative EUSFNA patients were followed for a mean of 403 days after negative EUS-FNA results without the development of malignancy. CONCLUSION: For patients undergoing EUS-FNA for a suspected pancreatic lesion, a negative or nondiagnostic FNA does not provide conclusive evidence for the absence of cancer. Patients for whom vascular invasion and lymphadenopathy are detected on EUS are more likely to have a true malignant lesion and should be followed closely. When a patient has been monitored for six months or more with no cancer being diagnosed, there appears to be much less chance that a pancreatic malignancy is present.

Amyloidosis presenting as lower gastrointestinal hemorrhage.

AL-Amyloid rarely presents in the gastrointestinal tract as acute gastrointestinal hemorrhage, especially in the absence of clinical disease elsewhere in the body. There are no reported cases of monoclonal gammopathy of undetermined significance progressing to AL-Amyloid presenting as lower gastrointestinal hemorrhage. We report a case of a patient initially diagnosed with monoclonal gammopathy of undetermined significance who progressed to AL-Amyloid over the course of 1 year. His progression resulted in primary colonic amyloidosis that manifested as lower gastrointestinal hemorrhage. The diagnosis was made by biopsy of a sigmoid plaque demonstrating necrotic material on histopathology. Amyloid deposition was seen on congo red and on birefringence. The bleeding stopped spontaneously without intervention and he was discharged his fourth day in the hospital. Further evaluation revealed no involvement in other organ systems. The plan is to treat with melphalan and dexamethasone. We conclude that early endoscopic examination and biopsy of the surrounding intestinal tissue is indicated when patients with monoclonal gammopathy of undetermined significance present with gastrointestinal hemorrhage to evaluate for the progression to AL-Amyloidosis. Treatment to prevent recurrent hemorrhage and further progression of the disease should be considered.

Hepatic Angiosarcoma: A Challenging Diagnosis.

Hepatic angiosarcoma (HA) accounts for 2% of primary liver tumors. Though rare, it is exceptionally deadly. The initial presentation of HA is nonspecific and no tumor markers have been associated with it. In general, liver function is maintained until later stages of the disease, often leading to diagnosis once the disease is already advanced or metastatic. In this report, we present the case of a 54-year-old male whose vague symptoms and non-diagnostic liver biopsy delayed the diagnosis of a rapidly progressing HA.

Pilot study using PET/CT as a novel, noninvasive assessment of disease activity in inflammatory bowel disease.

BACKGROUND: A pilot study was performed investigating the possibility that positron emission tomography (PET) activity using 18-fluorodeoxyglucose (FDG) with nearly simultaneous computerized tomography (CT) for anatomic accuracy would identify regions of active inflammation in both ulcerative colitis (UC) and Crohn's disease (CD). METHODS: Prospective clinical data was collected in 12 patients experiencing an exacerbation of their inflammatory bowel disease; 7 with CD and 5 with UC. A PET/CT scan (GE Discovery LS PET/CT scanner) was performed in all patients. Twenty patients undergoing PET/CT because of solitary pulmonary nodules served as controls. We graded the small bowel and 4 colon regions (ascending, transverse, descending, and rectosigmoid) with PET activity scores assigned to each region based on the amount of FDG uptake using the liver as the reference organ. RESULTS: In UC patients, PET activity was seen in 13 of 24 (52%) regions. There was high (23 of 24; 95.8%) correlation between PET activity and disease activity as determined by colonoscopy, disease activity indices, and radiology. In patients with CD, PET activity was seen in 19 of 32 (59.4%) regions. Again, there was a high (26 of 32; 81.3%) correlation between PET activity and clinical disease activity. Of the 20 controls, significant PET activity (Grades 2 and 3) was seen in only 2 of 100 regions (2%). CONCLUSIONS: We found that PET activity correlated well with active inflammation in both UC and CD, suggesting that this may be a noninvasive method of identifying disease activity in patients with inflammatory bowel disease.

Age-related changes in GluR2 and NMDAR1 glutamate receptor subunit protein immunoreactivity in corticocortically projecting neurons in macaque and patas monkeys.

A distinct subpopulation of neurons forming long corticocortical projections in the association neocortex is highly vulnerable to the degenerative process in Alzheimer's disease. However, the degree to which age-related molecular and morphologic alterations of identifiable neuronal populations reflects early cellular degeneration leading to functional deficits has not yet been fully investigated in the aging brain. We performed an immunohistochemical analysis of neurons forming short and long corticocortical projections in young and old monkeys using antibodies to the GluR2 and NMDAR1 glutamate receptor subunit proteins. Projection neurons differed in their expression of these receptor subunits, as GluR2 was less prevalent than NMDAR1 among retrogradely labeled neurons. Long and short corticocortical pathways in old animals demonstrated a considerable decrease in the proportions of projection neurons containing GluR2 and NMDAR1, an observation that was particularly consistent in the case of GluR2. No age-related differences were observed in distribution of neurofilament protein in either type of projection neurons. These data suggest that cortical neurons furnishing long and short corticocortical projections display consistent neurochemical changes during aging and that a differential decrease in cellular expression of glutamate receptor subunit proteins occurs. The fact that in aging these neurons have lower levels of GluR2 than in young individuals, but comparatively higher levels of NMDAR1 than GluR2, may render them prone to calcium-mediated excitotoxicity, which in humans may be related to the selective vulnerability of such neurons during the course of Alzheimer's disease. Also, it is apparent that age-related neuronal changes are quite subtle and involve subcellular components of the cortical circuits rather than major morphologic alterations.

Morphological alterations in neurons forming corticocortical projections in the neocortex of aged Patas monkeys.

Recent studies indicate that the cognitive processes mediated by the prefrontal cortex, such as working memory, are impaired during normal aging. These disturbances in cortical function may be a consequence of abnormalities in neocortical circuits, even though the numbers of cortical neurons are preserved in normal aging. We performed retrograde tract-tracing of cortical projections connecting the temporal cortex to the prefrontal cortex in combination with dye-filling and three-dimensional neuronal reconstructions in aged patas monkeys. Age-related changes affected the apparent complexity of the apical dendrites of projection neurons and caused a significant loss of dendritic spines at all levels of their dendritic trees. These results indicate that normal aging is accompanied by neuronal changes that are quite subtle, and possibly involves discrete cellular components of certain cortical neurons selectively rather than inducing major alterations such as cell death.