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Biomedical subjects

John Hart

Publications and source records attributed to John Hart.

18 recordsLinked to original sources
PubMed2003

cDNA microarray analysis of macroregenerative and dysplastic nodules in end-stage hepatitis C virus-induced cirrhosis.

Hepatocellular carcinoma is a common malignancy causing significant morbidity and mortality worldwide. In this study we use expression microarray technology to identify novel genes that consistently displayed altered expression levels in the earliest identifiable precursors to hepatocellular carcinoma, dysplastic and macroregenerative nodules. The gene expression profiles from nine patients with end-stage hepatitis C cirrhosis that contained a combined 11 dysplastic or macroregenerative nodules were compared to the patient's matched cirrhotic liver tissue. A total of 53 genes were consistently dysregulated in the patient liver specimens. Six of seven genes were validated by quantitative real-time reverse transcriptase-polymerase chain reaction, or by immunohistochemical studies performed on an independent set of lesions. The novel genes, including caveolin-1, semaphorin E, and FMS-like tyrosine kinase 3 ligand, have putative roles in carcinogenesis but have not been reported in hepatocellular carcinogenesis. Microarray expression analysis of dysplastic and macroregenerative liver nodules provide insight into the earliest changes in hepatocellular carcinogenesis.

Base Sequence↗
PubMed2003

Rosai-Dorfman disease presenting in the gastrointestinal tract.

Rosai-Dorfman disease (RDD) rarely presents a diagnostic challenge. However, unusual sites of presentation can cause confusion. We present a case of RDD of the colon in a symptomatic 51-year-old woman. The gastrointestinal tract is the organ system least commonly affected by RDD, with only 11 cases reported. Most cases have been found incidentally or at autopsy. The widespread use of endoscopic procedures makes it more likely that this entity will be encountered. Most patients with gastrointestinal tract involvement have evidence of widespread extranodal disease and have a protracted clinical course.

Adult↗
PubMed2002

Elevated protein expression of cyclin D1 and Fra-1 but decreased expression of c-Myc in human colorectal adenocarcinomas overexpressing beta-catenin.

Mutations of the adenomatous polyposis coli tumor suppressor gene, or its downstream target beta-catenin, have been implicated in the initiation of most sporadic human colorectal epithelial neoplasms. These mutations, in turn, lead to aberrant nuclear accumulation of beta-catenin and subsequent activation of the beta-catenin/Tcf transcription factor complex. In vitro studies utilizing cultured human colon cancer cell lines have identified c-myc, cyclin D1 and fra-1 as target genes of beta-catenin/Tcf signaling. In our study, 12 cases of human colorectal adenocarcinomas were examined by Western immunoblotting analysis and immunohistochemical staining to specifically investigate whether the protein expression of these target genes was indeed altered in vivo by beta-catenin dysregulation. The results show that the protein level of beta-catenin was significantly increased in all 12 tumors (3.4 +/- 1.0-fold increase compared to the control normal mucosa by Western immunoblotting, p < 0.05), and this increase was associated with positive nuclear staining by immunohistochemistry in 10 cases. Increased levels of expression of cyclin D1 and Fra-1 proteins were also demonstrated in every tumor (9.0 +/- 2.7 and 3.3 +/- 0.9-fold increases compared to normal mucosa, respectively). Surprisingly, the protein level of c-Myc was significantly decreased in all tumors examined by 49 +/- 19% (p < 0.05), but the c-myc mRNA level was increased in 8 of 12 tumors when compared to that in normal mucosa by RT-PCR. Immunohistochemical staining performed on these carcinomas and additional 27 colorectal carcinomas further demonstrated that the protein expression level of c-Myc and beta-catenin nuclear localization were not correlated. Moreover, 15 of 20 colorectal adenomas exhibited positive nuclear beta-catenin immunostaining, among which 11 also exhibited increased c-Myc protein expression. These data thus support the notion that upregulation of cyclin D1 and Fra-1 in human colorectal adenocarcinomas is driven by abnormally expressed beta-catenin. However, the regulation of c-myc expression in colorectal tumors appears to be more complex. While dysregulated beta-catenin may cause a transcriptional upregulation of the c-myc gene, the c-Myc protein expression appears to be further regulated by a posttranscriptional mechanism(s) during the process of neoplastic progression.

Adenocarcinoma↗
PubMed2002

Interactions between thalamic and cortical rhythms during semantic memory recall in human.

Human scalp electroencephalographic rhythms, indicative of cortical population synchrony, have long been posited to reflect cognitive processing. Although numerous studies employing simultaneous thalamic and cortical electrode recording in nonhuman animals have explored the role of the thalamus in the modulation of cortical rhythms, direct evidence for thalamocortical modulation in human has not, to our knowledge, been obtained. We simultaneously recorded from thalamic and scalp electrodes in one human during performance of a cognitive task and found a spatially widespread, phase-locked, low-frequency rhythm (7-8 Hz) power decrease at thalamus and scalp during semantic memory recall. This low-frequency rhythm power decrease was followed by a spatially specific, phase-locked, fast-rhythm (21-34 Hz) power increase at thalamus and occipital scalp. Such a pattern of thalamocortical activity reflects a plausible neural mechanism underlying semantic memory recall that may underlie other cognitive processes as well.

Brain Mapping↗
PubMed2002

A prospective study of motor recovery following multiple subpial transections.

A prospective study of motor recovery was undertaken in a patient scheduled to undergo multiple subpial transections (MST) of right sensorimotor cortex. Pre-transection, functional MRI (fMRI) and cortical stimulation mapping confirmed left hand motor control within right primary motor cortex. Immediately post-transection, behavioral testing demonstrated preserved strength bilaterally but decreased dexterity in the left hand. Seven weeks post-transection, dexterity returned to normal and left hand finger tapping corresponded with multiple bilateral foci of fMRI activation. At 16 weeks, fMRI activation returned to pre-transection levels. These data indicate that cortical injury due to MST resulted in the temporary recruitment of distant cortical sites which presumably subserved normal motor function during recovery.

Adult↗
PubMed2002

Large-scale cortical displacement of a human retinotopic map.

The aim of the current study was to determine the retinotopic organization of a patient with congenital cortical dysgenesis and normal visual function. Using functional magnetic resonance imaging (fMRI), detailed retinotopic maps corresponding to the four visual field quadrants were projected onto cortical surfaces. Similar to control subjects, the upper right visual field mapped onto ventral left hemisphere and was retinotopically organized. The lower right visual field's cortical representation was also retinotopically organized, yet was displaced many centimeters anteriomedially. Moreover, the entire left visual field was represented in non-retinotopically organized islands in both hemispheres. These results indicate retinotopic maps can shift in both location and topography illustrating cortical reorganization presumably due to either cortical dysgenesis or functional displacement. NeuroReport

Adult↗
PubMed2002

Object activation from features in the semantic system.

The human brain is thought to elicit an object representation via co-activation of neural regions that encode various object features. The cortical regions and mechanisms involved in this process have never been elucidated for the semantic system. We used functional magnetic resonance imaging (fMRI) to evaluate regions activated during a task designed to elicit object activation within the semantic system (e.g., presenting the words "desert" and "humps" with the task to determine if they combine to form an object, in this case a "camel"). There were signal changes in the thalamus for word pairs that activated an object, but not for pairs that (a) failed to activate an object, (b) were simply semantically associated, or (c) were members of the same category. These results suggest that the thalamus has a critical role in coordinating the cortical activity required for activating an object concept in the semantic system.

Adult↗
PubMed2002

Object activation in semantic memory from visual multimodal feature input.

The human brain's representation of objects has been proposed to exist as a network of coactivated neural regions present in multiple cognitive systems. However, it is not known if there is a region specific to the process of activating an integrated object representation in semantic memory from multimodal feature stimuli (e.g., picture-word). A previous study using word-word feature pairs as stimulus input showed that the left thalamus is integrally involved in object activation (Kraut, Kremen, Segal, et al., this issue). In the present study, participants were presented picture-word pairs that are features of objects, with the task being to decide if together they "activated" an object not explicitly presented (e.g., picture of a candle and the word "icing" activate the internal representation of a "cake"). For picture-word pairs that combine to elicit an object, signal change was detected in the ventral temporo-occipital regions, pre-SMA, left primary somatomotor cortex, both caudate nuclei, and the dorsal thalami bilaterally. These findings suggest that the left thalamus is engaged for either picture or word stimuli, but the right thalamus appears to be involved when picture stimuli are also presented with words in semantic object activation tasks. The somatomotor signal changes are likely secondary to activation of the semantic object representations from multimodal visual stimuli.

Adult↗
PubMed2002

First two patients with ulcerative colitis who developed classical thrombotic thrombocytopenic purpura successfully treated with medical therapy and plasma exchange.

The association of ulcerative colitis (UC) and thrombotic thrombocytopenic purpura (TTP) is rare. Only one prior patient with these two syndromes has been reported in the literature. In that case, splenectomy and proctectomy were performed to control the symptoms of TTP. We present two patients with UC who developed TTP and were successfully treated with multiple plasma exchanges (PEXs) in conjunction with medical therapy without the necessity for surgical intervention. Acquired TTP may be another extraintestinal autoimmune feature of UC. TTP in association with UC may be refractory to high-dose steroids and PEX, possibly requiring vincristine and splenectomy, as in the one previously reported case, to achieve remission.

Adult↗
PubMed2002

Neural activation during an explicit categorization task: category- or feature-specific effects?

Previous lesion-deficit and functional imaging studies have suggested that there are distinct category-specific regions within the human brain. Using functional magnetic resonance imaging, we tested this claim with a task in which participants decided if two items, represented by words, were members of the same category. Signal changes detected for all pairs of items that were from the same category and for tool pairs were found in rostromedial BA 6, rostral cingulate, and at the BA 6/44 and BA 45/46 junctions. Activation was seen in BA 6 and the left BA 6/44 junction for fruits and vegetables pairs and only in rostromedial BA 6 for animal pairs. The common signal changes in the frontal lobes (BA 6/44) for the categories of fruits and vegetables and tools suggest that this region may be organized in a feature-specific, as opposed to a category-specific, manner.

Adult↗
PubMed2002

The effect of age on rate of functional recovery after intracarotid amobarbital injection.

PURPOSE: The duration of the drug effect during the intracarotid amobarbital procedure (IAP) is an important factor when considering the prioritization of behavioral testing during the IAP. Previous studies of thiopental, a barbiturate similar to sodium amobarbital, found that age and gender significantly affect the dose required to induce anesthesia, such that younger patients require higher dosage. METHODS: A total of 55 patients who underwent the IAP procedure at Johns Hopkins Hospital were included in the study (110 hemispheric injections). The patient group included 30 female and 25 male patients, ranging in age from 11 to 50 years. To determine if a higher dose of sodium amobarbital was needed for younger patients during the IAP, we analyzed the time to return to preinjection EEG baseline status and time to return to 5/5 strength as a function of patient age and gender. RESULTS: We found that younger patients (11-20 years old) returned to preinjection baseline EEG status and full (5/5) strength faster than older patients. No gender difference was found. CONCLUSIONS: The sodium amobarbital effect during IAP dissipates faster in young patients. Consideration of this difference in rate of recovery in 11-to 20-year-old patients has important clinical implications in terms of prioritizing behavioral testing.

Adolescent↗
PubMed2002

Are ulcers a marker for invasive carcinoma in Barrett's esophagus? Data from a diagnostic variability study with clinical follow-up.

OBJECTIVES: We correlated follow-up information from 138 patients with Barrett's esophagus and varying degrees of dysplasia with the presence of ulcers. METHODS: A group of pathologist participants were asked to contribute patients' initial biopsy slides showing Barrett's esophagus (BE) without dysplasia and with epithelial changes indefinite for dysplasia, low grade dysplasia (LGD), high grade dysplasia (HGD), and adenocarcinoma. From the initial 250 cases used for a diagnostic reproducibility study, follow-up information was available for 138 patients. RESULTS: There were 44 cases submitted as BE, 22 as BE with epithelial changes indefinite for dysplasia, 26 as BE with LGD, 33 as BE with HGD, and 13 as BE with adenocarcinoma. Ulcers were present in 35/138 cases (25%), including 3/44 cases of BE without dysplasia (7%), 2/22 cases of BE with epithelial changes indefinite for dysplasia (9%), 0/26 cases of BE with LGD (0%), 10/33 cases of BE with HGD (30%), and 7/13 cases of BE with adenocarcinoma (54%). On follow-up, there were no invasive carcinomas detected among the BE without dysplasia group (median follow-up = 38.5 months). Adenocarcinomas were detected in 4/22 cases (18%) submitted as BE with epithelial changes indefinite for dysplasia at 19, 55, 60, and 62 months and in 4/26 cases (15%) of BE with LGD at 9, 9, 11, and 60 months. None of these carcinomas occurred in cases in which an ulcer was present in the initial biopsy specimen. Among the 33 HGD cases, 20 (60%) were found to have adenocarcinoma on subsequent resection specimens. The presence of an ulcer with HGD increased the likelihood of finding carcinoma in the resection specimen, as 8/10 biopsies (80%) of HGD patients with ulcers had carcinoma, compared to 12/23 biopsies (52%) of HGD patients without ulcers. All of the cases interpreted as adenocarcinomas on biopsy were found either to have invasive carcinoma on esophageal resection or to have metastases that were demonstrated in unresectable patients. CONCLUSION: If an ulcer accompanies HGD in a biopsy specimen from a patient with BE, it is likely that invasive carcinoma is also present at that time.

Adenocarcinoma↗
PubMed2002

Natural history of mucinous ductal ectasia of the pancreas: a case report and review of the literature.

Mucinous ductal ectasia (MDE) remains a less known disease entity of the pancreas. In an attempt to further characterize its natural history, we report the case of a 68-yr-old man with MDE initially unrecognized in an abdominal CT obtained 5 yr before diagnosis and resection. Furthermore, we have reviewed available case reports in the English literature to clarify the differences between MDE and mucinous cystic neoplasm, two entities that have been frequently confused for one another. MDE is an uncommon disorder of the pancreas characterized by dilated primary and secondary ducts filled with thick mucus that appear as a mass or cyst by ultrasound or CT. ERCP demonstrates a patulous duodenal papilla with extruding mucin from the orifice. Histological changes within the ducts reveal hyperplasia, adenoma, or adenocarcinoma. The recognition of MDE is essential because early detection allows for curative surgical resection of these usually latent and indolent pancreatic neoplasms. Further characterization of MDE and additional longitudinal studies are necessary to elucidate its natural history and define its optimal management.

Adenocarcinoma, Mucinous↗
PubMed2002

Tailored cognitive testing with provocative amobarbital injection preceding AVM embolization.

BACKGROUND AND PURPOSE: Transarterial embolization of cerebral arteriovenous malformations (AVMs) has been associated with postprocedural neurologic complications in 7-39% of patients. We sought to determine whether a method of targeted neurologic and cognitive testing during AVM embolization reduces the incidence of focal cognitive and other neurologic deficits associated with the procedure. METHODS: A cognitive neurologist extensively examined 12 patients prior to AVM embolization. In each patient, a battery of tests tailored to their specific abilities was developed by using stimuli selected from standard and experimental cognitive tests to probe specific brain regions related to the location of the AVM. In each feeder vessel to be embolized, a 50-mg bolus of sodium amobarbital was superselectively administered through a microcatheter; this was followed immediately by neurologic and cognitive testing with the tailored battery. After testing, the position of the microcatheter tip was checked with fluoroscopy. If the provocative test results were negative, the evaluated feeder was embolized with N-butyl cyanoacrylate glue. RESULTS: Although results with 27 of 29 provocative amobarbital injections were negative, results with two injections in two different individuals revealed cognitive deficits during tailored provocative testing. In both, the evoked deficits resolved with dissipation of the amobarbital effect; the feeder vessels were not embolized. Neurologic and cognitive evaluation after each of 27 embolizations revealed no major or minor deficits. CONCLUSION: In our experience, provocative amobarbital testing prior to AVM embolization was helpful in identifying vascular territories where embolization may lead to neurologic and cognitive deficits.

Adult↗
PubMed2002

Ursodeoxycholic acid inhibits the initiation and postinitiation phases of azoxymethane-induced colonic tumor development.

Colonic tumorigenesis involves the processes of initiation and promotion/progression from normal epithelial cells to tumors. Studies in both humans and experimental models of colon cancer indicate that secondary bile acids promote tumor development. In contrast, we have demonstrated previously that another bile acid, ursodeoxycholic acid (UDCA), inhibits the development of azoxymethane (AOM)-induced colon cancer in rats. More recently, we have shown that UDCA inhibits AOM-induced hyperproliferation, and aberrant crypt formation and growth. In our previous studies, we supplemented UDCA throughout the experiment. The efficacy of a chemopreventive agent may depend on the timing of administration, which has important clinical implications. In the present investigation, we examined the ability of UDCA, when administered only in the initiation or the promotion/progression phase, to block tumor development. Male Fisher 344 rats were divided in a 2 x 3 factorial design, with animals receiving AOM or vehicle, and fed an unsupplemented diet or diet supplemented with 0.4% UDCA in the initiation or promotion/progression phase. Thirty-two weeks later, rats were sacrificed and tumor histology determined, and colons were examined for aberrant crypt foci (ACF). In the carcinogen-treated dietary control group, tumor incidence was 72.3%, and tumor multiplicity was 1.9 tumors per tumor-bearing rat. UDCA, in the initiation or promotion/progression phase, significantly decreased tumor incidence to 46.2% and 38.4% (P < 0.05), respectively; and tumor multiplicity to 1.4 and 1.3 tumors per tumor-bearing rat (P < 0.05), respectively. UDCA did not alter tumor size, histology, or location, although there were trends for smaller tumors and less advanced histological grades in the group given UDCA during the promotion phase. UDCA, in the initiation but not the promotion phase, inhibited ACF formation and growth. In summary, UDCA significantly inhibited AOM-induced colonic carcinogenesis during either tumor initiation or in the promotion/progression phase. In contrast, UDCA inhibited ACF formation only when administered in the initiation phase, suggesting that the mechanisms of chemoprevention by this bile acid differ in these two phases.

Animals↗
PubMed2002

Ursodeoxycholic acid and F(6)-D(3) inhibit aberrant crypt proliferation in the rat azoxymethane model of colon cancer: roles of cyclin D1 and E-cadherin.

We have previously demonstrated that ursodeoxycholic acid(UDCA) and a fluorinated analogue of vitamin D(3), F(6)-D(3),inhibited colonic carcinogenesis in the azoxymethane (AOM) model. Generalized colonic mucosal hyperproliferation and aberrant crypt foci (ACF) are intermediate biomarkers of colon cancer. Using these biomarkers, in this study we examined the anticarcinogenic mechanisms of these chemopreventive agents. Rats were maintained on AIN-76A chow or supplemented with 0.4% UDCA or F(6)-D(3) (2.5 nmol/kg chow) and treated weekly with AOM 20 mg i.p./kg wt or saline x 2 weeks. F(6)-D(3) was continued for an additional 2 weeks and UDCA for the duration of the study. At 40 weeks, animals received bromodeoxyuridine (BrdUrd) i.p. 2 h before sacrifice. A portion of each tumor was fixed in formalin and the remainder flash frozen. Colons were divided longitudinally and half-fixed in formalin and half in ethanol. The size and location of methylene blue-stained ACF were recorded. Cell proliferation (BrdUrd labeling) and apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling assay) were measured in colonic crypts and tumors. Protein expression levels of several regulators of cell proliferation were analyzed by immunostaining and Western blotting. Colonic crypt cyclin D1 and E-cadherin mRNA levels were measured by real-time PCR. In saline injected controls, neither UDCA nor F(6)-D(3) alone had any effect on cytokinetic parameters or on the expression of mitogenic regulators. AOM significantly increased the proliferation (percentage of BrdUrd-positive cells) of both ACF (23.1 +/- 1.7%) and non-ACF crypts (17.6 +/- 1.6%), compared with normal colonic crypts (4.5 +/- 0.8%; P < 0.05). This hyperproliferation was accompanied by a 5-fold increase in cyclin D1 and >50% decrease in E-cadherin protein (P < 0.05) in ACF, both of which are predicted to be growth-enhancing alterations. UDCA and F(6)-D(3) significantly (P < 0.05) inhibited AOM-induced crypt cell hyperproliferation, ACF development, and tumor burden. These chemopreventive agents also significantly blocked AOM-induced alterations in cyclin D1 and E-cadherin protein in ACF and tumors. In ACF, changes in mRNA levels of cyclin D1, but not E-cadherin, paralleled alterations in protein expression. Cyclooxygenase-2 and inducible nitric oxide synthase were increased in AOM tumors but not in ACF, and these changes were blocked by UDCA and F(6)-D(3). UDCA and F(6)-D(3) significantly inhibited ACF development and hyperproliferation, in part, by preventing carcinogen-induced alterations in cyclin D1 and E-cadherin. In established tumors, UDCA and F(6)-D(3) also limited inductions of cyclooxygenase-2 and inducible nitric oxide synthase, which together with their effects on cyclin D1 and E-cadherin, contribute to their chemopreventive actions.

Animals↗
PubMed2000

Right Hemisphere Language Dominance in a Right-Handed Patient with Late-Onset Seizures.

Right hemisphere language dominance is rare in right-handed individuals and usually the result of language transfer associated with early left hemisphere pathology. We studied a 33-year-old right-handed man, with a normal MRI scan, who developed left frontal lobe seizures at age 15 years. Language lateralization testing by intracarotid amobarbital injection and dichotic listening showed the patient to be strongly right hemisphere language dominant. The clinical features of this patient do not fit the profile of pathology-induced language transfer, but instead suggest that he was right hemisphere language dominant before developing seizures. This case underscores the importance of language lateralization testing in patients who are candidates for seizure surgery, even if they are strongly right-handed and have late-onset seizures, features usually associated with left hemisphere language dominance. One implication is that the incidence of right hemisphere language dominance in the right-handed population may be underestimated.

Journal Article↗