mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.

Transaldolase deficiency predisposes to chronic liver disease progressing from cirrhosis to hepatocellular carcinoma (HCC). Transition from cirrhosis to hepatocarcinogenesis depends on mitochondrial oxidative stress, as controlled by cytosolic aldose metabolism through the pentose phosphate pathway (PPP). Progression to HCC is critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Although AR inactivation blocked susceptibility to hepatocarcinogenesis, it enhanced growth restriction, carbon trapping in the non-oxidative branch of the PPP and failed to reverse the depletion of glucose 6-phosphate (G6P) and liver cirrhosis. Here, we show that inactivation of the TAL-AR axis results in metabolic stress characterized by reduced mitophagy, enhanced overall autophagy, activation of the mechanistic target of rapamycin (mTOR), diminished glycosylation and secretion of paraoxonase 1 (PON1), production of antiphospholipid autoantibodies (aPL), loss of CD161+ NK cells, and expansion of CD38+ Ito cells, which are responsive to treatment with rapamycin in vivo. The present study thus identifies glycosylation and secretion of PON1 and aPL production as mTOR-dependent regulatory checkpoints of autoimmunity underlying liver cirrhosis in TAL deficiency.

Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.

Oxidative stress modulates carcinogenesis in the liver; however, direct evidence for metabolic control of oxidative stress during pathogenesis, particularly, of progression from cirrhosis to hepatocellular carcinoma (HCC), has been lacking. Deficiency of transaldolase (TAL), a rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP), restricts growth and predisposes to cirrhosis and HCC in mice and humans. Here, we show that mitochondrial oxidative stress and progression from cirrhosis to HCC and acetaminophen-induced liver necrosis are critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Both TAL and AR are confined to the cytosol; however, their inactivation distorts mitochondrial redox homeostasis in opposite directions. The results suggest that AR acts as a rheostat of carbon recycling and NADPH output of the PPP with broad implications for disease progression from cirrhosis to HCC.

Histological and angiographic effects of a pulsed holmium:YAG laser in normal and atherosclerotic human coronary arteries and aorta.

OBJECTIVE: The aims were (1) To determine the histological and angiographic effects of holmium:YAG laser energy delivered through clinical multifibre laser catheters on fresh cadaveric coronary arteries; and (2) to relate the placement of optical fibres in the catheter to patterns of tissue ablation in cadaveric aorta. METHODS: Eight fresh cadaveric hearts and segments of aorta were used. Hearts were mounted on a new pressure perfusion device. The laser catheter was delivered over a guidewire in the lumen until it met an area of resistance. The coronary artery lumen was perfused at approximately 100 mm Hg mean pressure. These arterial areas were identified on angiography, marked, and then exposed to laser energy in the range 600-3000 mJ.mm-2. Normal and atherosclerotic areas of fresh cadaveric aortic strips were exposed to increasing laser energies using either constant or increasing fluence. Coronary arteries were pressure perfused with formalin for 18-24 h at 100 mm Hg mean pressure, and aortic strips were immersed in 5% formalin. Light and scanning electron microscopy studies were carried out. RESULTS: There were no perforations or dissections by angiography in the fresh coronary arteries. One of 15 normal coronary artery segments and 10 of 16 of the pressure perfused, fixed, atherosclerotic coronary artery segments showed thermal changes associated with atherosclerotic plaque ablation. In aortic tissue, thermal effects extended 0 to 0.6 mm lateral to the ablated crater. Acoustic effects were seen only in the aortic strips after ablation at fluences > 1000 mJ.mm-2. The "dead spaces" around the optical fibres in the catheter resulted in significant amounts of coagulated tissue fragments remaining in the crater. CONCLUSIONS: Holmium:YAG laser energy delivered through multifibre catheters ablated atherosclerotic tissue in coronary arteries with minimal damage to the normal walls. The cadaveric coronary artery perfusion apparatus is useful for assessing catheter delivery and mobility and the effects of laser energy on the coaxially orientated normal and atherosclerotic coronary arterial wall.

Warfarin-related purple toes syndrome and cholesterol microembolization.

The "purple toes syndrome" is a rare complication of oral anticoagulant therapy. Four patients who presented with "purple toes syndrome" several weeks after warfarin therapy was initiated are described. The diagnosis of cholesterol microembolization was made by biopsy in three cases. Malignant hypertension and renal failure developed in two patients who died within three to six months of onset of purple toes. Postmortem examination in one of these patients showed widespread cholesterol microembolization. Renal failure has not developed in the other two patients, who are doing well. These biopsy and autopsy results suggest that the warfarin-related "purple toes syndrome" is due to cholesterol microembolization.

Inheritance of osteosarcoma and Paget's disease of bone: a familial loss of heterozygosity study.

Pagetoid osteosarcoma is a complication of Paget's disease of bone. Sarcomatous transformation is most often seen in severe, long-standing Paget's disease. Familial clustering of Paget's disease has been described with apparent autosomal dominant inheritance with high penetrance by the sixth decade. Although definitive proof of the specific gene involved remains elusive, some researchers have shown loss of heterozygosity in a region of chromosome 18q in a relatively high percentage of studied patients affected with either Paget's disease alone, in Pagetoid osteosarcoma, and in uncomplicated osteosarcoma. Our patient was diagnosed with Pagetoid osteosarcoma and had a first-degree relative with history of the same. We hypothesized that our patient's tumor samples might contain a similar genetic abnormality. Our analysis of several polymorphic markers from the chromosome 18q21-22 region showed loss of maternally inherited alleles throughout the region. This finding is similar to those described previously and provides further evidence of a susceptibility region relating to this disease. This report describes a father and son, their young ages at diagnosis of Pagetoid sarcoma, the identical sites of disease involvement, and a loss of heterozygosity study illustrating the inheritance of the presumed defective gene.

Lipogranulomas and gold in the liver in rheumatoid arthritis.

Liver biopsies have been performed routinely as part of a protocol to evaluate methotrexate therapy in severe rheumatoid arthritis. All patients in the study had failed standard medical therapy, including gold treatment. Twenty-three of 41 patients (56%) had well-formed lipogranulomas (LGs) in the lobules, compared with an incidence of approximately 5% in our general biopsy population. Twenty-seven of 41 patients (66%) had a unique pigment in their livers. In 20 of these, the pigment was in LGs; in the seven patients with pigment not associated with lobular LG, it was found in lipid droplets in portal triads. The pigment varied from irregular pale brown granules slightly larger than those of hemosiderin, to smaller black round granules. Lipogranuloma-associated pigment of this type is an unusual finding, reminiscent of argyria. There was a variable appearance upon polarization, the black granules at times being strikingly refractile. There was a positive correlation between the prominence of LG and the quantity of pigment. The pigment resembled that described with gold deposition in other tissues. Radiographic microanalysis of both brown and black granules was performed in three cases. Characteristic spectra (energy-dispersive spectroscopy) demonstrated the presence of gold in each case. Silver was not identified. The high incidence of LG may reflect the frequent administration of gold in an oily vehicle. Gold may remain trapped in the liver for a prolonged time. Thus far, we have not detected any adverse effect from the presence of LG-associated gold.

Behavioral stress alters coronary vascular reactivity in borderline hypertensive rats.

BACKGROUND: Behavioral stress has been proposed to contribute to the occurrence of myocardial ischemia. Objective To investigate the effect of chronic exposure to behavioral stress on the function and structure of the coronary artery of borderline hypertensive rats (BHR). DESIGN: BHR were either exposed to an air-jet stress for 2 h/day for 10 days or kept in their cage for 10 days. METHODS: After 10 days, hemodynamic measurements in conscious animals were recorded, and their hearts were removed for isolation of a left ventricular coronary artery for functional studies or for fixation by retrograde perfusion for study with scanning electron microscopy. Vascular reactivity was measured in isolated coronary arteries (approximately 250 microm) maintained at an intraluminal diameter of 40 mmHg while the intraluminal diameter was recorded continuously. RESULTS: The resting mean arterial pressure and heart rate in conscious, unrestrained BHR were not altered significantly by exposure to 10 days of 2 h/day air-jet stress. Coronary artery relaxation in response to the endothelium-dependent vasodilator acetylcholine was impaired in rats exposed to the air-jet stress compared with that in controls. An attenuated response to exogenous nitric oxide in coronary arteries from stressed BHR was confirmed by the finding of a reduced sensitivity to nitroprusside, which releases nitric oxide independently from the endothelium. However, relaxation of coronary arteries in response to isoproterenol, which acts independently from nitric oxide, was not altered. Coronary artery contraction in response to endothelin-1 and phenylephrine was not altered in vessels taken from BHR exposed to behavioral stress compared with that in vessels from control rats. Scanning electron microscopy of the endothelial surface of the septal coronary artery showed no difference between vessels from control and stressed BHR. CONCLUSION: These results indicate that behavioral stress impairs endothelium-dependent and nitric oxide-mediated coronary relaxation, but does not alter alpha1-adrenoceptor or endothelin-1-mediated contraction. By impairing coronary artery vascular relaxation, chronic exposure to behavioral stress may contribute to myocardial ischemia.

Evidence that epidermal alloantigen Epa-1 is an immunogen for murine heart as well as skin allograft rejection.

Epa-1 is a non-H-2 mouse alloantigen defined by MHC-restricted, CD8+ cytotoxic T cells. In vitro it is a strong determinant for the lysis of epidermal cells, fibroblasts, and macrophages but not lymphocytes, and in vivo it functions as a target for skin allograft rejection and cutaneous graft-versus-host reactions. Genetically, Epa-1 appears to be the nonpolymorphic manifestation of a loss mutation. The establishment of C3H.Epa-1 (Epa), an Epa-1+ congenic strain on the Epa-1- C3H/HeJ (C3H) inbred strain background, facilitated the investigation of the role of Epa-1 in skin and heart allograft rejection. C3H females and males rejected first-set Epa skin grafts with median survival times (MSTs) of 20 and 30 days, respectively. However, there was a strong factor of immunization, because all second-set skin allografts were rejected by hosts of both sexes within 10 days. In contrast, all Epa hosts of both sexes permanently accepted C3H skin allografts, consistent with Epa-1 arising from a loss mutation. C3H hosts of both sexes rejected primarily vascularized first-set Epa heart allografts in similar tempo to first-set Epa skin allografts, with MSTs of about 30 days. However, in contrast to the accelerated rejection of skin allografts, sensitized C3H hosts rejected Epa heart allografts in chronic fashion, with some transplants showing very prolonged survival. Thus, Epa-1 is a relatively strong determinant of skin allograft rejection but a weaker determinant of heart allograft rejection.

Ultrafast computed tomography in experimental pulmonary embolism.

Computed tomography (CT) has proven useful in the diagnosis of central pulmonary embolism; however, its ability to detect peripheral emboli has not been established. The authors evaluate the usefulness of ultrafast CT (UFCT) in detecting experimental peripheral pulmonary emboli. Three Gelfoam emboli measuring 0.7 x 1.5 cm were introduced into the pulmonary arteries of each of seven dogs, and contiguous, 3-mm, axial UFCT images from the lung apex to the base were obtained after the administration of a contrast bolus. After scanning, the dogs were killed, and the locations of the emboli were determined by a pulmonary pathologist blinded to the imaging results. Concomitantly, the locations of the emboli on the UFCT images were determined by consensus of three chest radiologists blinded to the autopsy results. All 21 emboli were identified on UFCT images; the locations of the emboli corresponded exactly with the autopsy findings. The authors conclude that UFCT can reliably detect Gelfoam emboli in second- to fourth-division pulmonary vessels. Further studies are needed to determine if in vivo blood clots can be similarly visualized.

Contrast-enhanced thin slice ultrafast computed tomography for the detection of small pulmonary emboli. Studies using autologous emboli in the pig.

RATIONALE AND OBJECTIVES: Ultrafast computed tomography (UFCT) has proven useful, but is of limited practical application in the diagnosis of central pulmonary embolism; however, its ability to detect more peripheral emboli has not been established. In this study, the use of contrast-enhanced UFCT images for the detection of autologous peripheral pulmonary emboli in the pig is evaluated. METHODS: A single autologous embolus measuring 0.7 x 1.5 cm was introduced into the superior vena cava of eight pigs. Contiguous, 3-mm axial UFCT images from the lung apex to the base were obtained before and after the introduction of the embolus. After scanning, the pigs were killed, and the thorax was removed intact and was frozen in a dry ice-alcohol mixture. Later, the thorax was sliced at 10-mm thicknesses, and the locations of the emboli were determined by a pulmonary pathologist blinded to the imaging results. Concomitantly, the locations of the emboli were determined by consensus of three chest radiologists blinded to the autopsy results. RESULTS: In 6 of 8 animals with emboli, the embolus location correlated exactly with the autopsy findings. In one, the embolus was on the same side, but 1.6 cm further distal. In the other, a marking suture was identified, but no clot was identified on the pathologic or UFCT examination. In the eight animals scanned before the introduction of the embolus, no embolus was found. Interobserver agreement was 100%. CONCLUSIONS: Ultrafast computed tomography has the potential to detect autologous emboli in second- to fourth-division pulmonary vessels. Further studies are needed to determine if in vivo emboli can be similarly visualized.

Extraskeletal myxoid chondrosarcoma of the pleura. Report of a case clinically simulating mesothelioma.

A primary extraskeletal myxoid chondrosarcoma of the pleura that clinically mimicked a malignant mesothelioma in a 66-year-old man with a history of asbestos exposure is described. Although exceedingly rare in this location, the characteristic histologic features, immunohistochemical reactivities, and ultrastructural features support the diagnosis of extraskeletal myxoid chondrosarcoma. Many ferruginous (asbestos) bodies consistent with the exposure history were found in the lung tissue sections and confirmed by energy-dispersive spectrometry. This case demonstrates an unusual pleural primary neoplasm associated with asbestos.

Black thyroid syndrome: exaggeration of a normal process?

Coal-black thyroid discoloration usually is identified in patients receiving chronic minocycline therapy. This report concerns the use of light microscopic, electron microscopic, and energy dispersion spectroscopy of thyroid pigments in three separate situations: minocycline-associated black thyroid; idiopathic black thyroid; and normally pigmented thyroid glands. One of the pigments, which is found in each situation, is best described as neuromelanin. This melanin pigment, like lipofuscin, appears to accumulate with advancing age. Pigment accumulation, therefore, is a normal process in the thyroid gland. Accelerated pigment accumulation occurs with minocycline therapy but can uncommonly be seen without associated minocycline treatment. Possible mechanisms for the development of these pigments in normal and black thyroid glands are discussed. Minocycline-associated pigment is also described in substantia nigra and atherosclerotic plaques.

Incidental prostate adenocarcinoma in a thirty-year-old Native American.

We report a case of prostatic adenocarcinoma in a thirty-year-old Native American. The tumor was an incidental autopsy finding. We speculate on the biological and clinical significance of prostate tumors in young males.

Selective catecholamine depletion of structures along the ventral lamina terminalis: effects on experimentally-induced drinking and pressor responses.

Ablation of the periventricular tissue of the anteroventral third ventricle (AV3V) or injection of the chemical neurotoxin, 6-hydroxydopamine (6-OHDA), into the structures along the ventral lamina terminalis will produce deficits in drinking and pressor responses to exogenous angiotensin II (ANG II). Centrally-applied 6-OHDA has been shown to result in widespread depletions of both adrenergic (i.e. both noradrenaline and adrenaline-containing) and dopaminergic neurons. Questions arise, therefore, as to whether a dopaminergic or adrenergic depletion is critical and the locus where reductions must occur. The present experiment was designed to investigate the specificity of the effects of 6-OHDA administration into lamina terminalis-associated structures on ANG II-induced drinking and pressor responses. The nature of the depletion was manipulated with desmethylimipramine (DMI), a drug which blocks the uptake of 6-OHDA into adrenergic but not dopaminergic nerve terminals and thereby spares adrenergic elements. The experimental results indicate that 6-OHDA administration into structures of the ventral lamina terminalis produced ANG II response deficits and marked reductions in catecholamine histofluorescence in the regions of the injection sites. In contrast, pretreatment with DMI protected against the 6-OHDA-produced functional deficits and minimized the effects on histofluorescence. These findings are consistent with the interpretation that adrenergic but not dopaminergic neurons must be present in the structures of the ventral lamina terminalis in order to elicit normal angiotensin-induced drinking and pressor responses.

Localized injections of 6-hydroxydopamine into lamina terminalis-associated structures: effects on experimentally induced drinking and pressor responses.

Electrolytic lesions of tissues surrounding the anteroventral third ventricle (AV3V) or injections of the chemical neurotoxin, 6-hydroxydopamine (6-OHDA) into the lateral cerebral ventricles result in virtually identical deficits in response to a variety of dipsogenic and pressor challenges. These observations have led to the hypothesis that the integrity of catecholamine (CA) projections into the AV3V region is a prerequisite for elicitation of these thirst and blood pressure responses. This hypothesis was tested in 6-OHDA-injected rats following protocols designed to deplete CA's in discrete structures associated with the lamina terminalis. Post-injection response deficits, coupled with histofluorescent assessments of CA depletions in specific anterior forebrain nuclei, support the stated hypothesis. In addition, the findings indicate that thirst deficits to systemic as well as central dipsogenic challenges are both selective and dissociable and that 6-OHDA lesions of any of the more ventrally situated target nuclei result in significantly attenuated blood pressure responses to centrally injected angiotensin II.

Fetal noradrenergic transplants into amine-depleted basal forebrain nuclei restore drinking to angiotensin.

6-Hydroxydopamine-induced catecholamine denervations in the organum vasculosum of the lamina terminalis and the median preoptic nucleus attenuate drinking responses to systemic angiotensin II (ANG II) injections. Transplanting catecholamines in these nuclei using fetal noradrenergic (NE) cell suspension restores ANG II-elicited thirst. These results emphasize the functional importance of NE neuronal systems in nuclei of the anteroventral third ventricle (AV3V) in mediating ANG II-induced drinking behaviors.

Nonpigmented papillary carcinoma in a black thyroid gland.

A case of papillary thyroid carcinoma occurring in a 27-year-old man with black thyroid syndrome is reported. The tumor, in contrast to the remaining thyroid, was not pigmented. The significance and potential utility of the differential pigmentation are discussed.

Suprasellar monomorphous pilomyxoid neoplasm: an ultastructural analysis.

The authors report 3 patients, 2 children and 1 adult, each of whom presented with an unusual myxoid lesion reminiscent of pilocytic astrocytoma but with other features of myxopapillary ependymoma. The magnetic resonance imaging findings in all cases showed a diffusely contrast-enhancing suprasellar mass focally extending into the third ventricle. Involvement of adjacent structures was more extensive in both infants. By light microscopy, all were composed of a monotonous population of cells with delicate piloid-like processes, loosely arranged within a prominent myxoid background. Focally, the neoplastic cells converged upon small blood vessels in pseudorosette-like formations. These histomorphologic features are identical to those of the recently described astrocytoma with monomorphous pilomyxoid features. In addition, the individual tumor cells showed strong cytoplasmic immunoreactivity with antibodies to glial fibrillary acidic protein (GFAP) and vimentin, as well as nuclear and cytoplasmic staining with S-100. All stained positive for synaptophysin and negative for chromogranin. By electron microscopy, the tumor cells were bipolar with elongated processes and apical surfaces displaying microvilli, cytoplasmic blebs and rare cilia. Vesicles and coated pits were seen, as were occasional synaptoid complexes. The current study serves to expand our clincopathologic experience with this rare and enigmatic lesion, with particular attention given to the ultrastructural characteristics.

Glial fibrillary acidic protein expression in pleomorphic adenoma, chordoma, and astrocytoma. A comparison of three antibodies.

Glial fibrillary acidic protein (GFAP) is a major constituent of glial cytoplasmic intermediate filaments. Glial fibrillary acidic protein expression has been accepted as a marker of astroglial differentiation or origin. However, GFAP expression has been demonstrated in a variety of normal and neoplastic tissues outside the central nervous system, including pleomorphic adenomas, chordomas, bone, and cartilage. It has been postulated that coexpression of GFAP and vimentin in neoplastic myoepithelial cells in pleomorphic adenomas reflects early chondroid differentiation. Glial fibrillary acidic protein expression in chondromyxoid and chordoid tumors was studied in formaldehyde solution-fixed, paraffin-embedded sections of 20 pleomorphic adenomas and 10 chordomas by the immunoperoxidase method with the use of commercially available monoclonal (n = 2) and polyclonal (n = 1) antibodies. All pleomorphic adenomas and chordomas demonstrated expression of GFAP with the use of the polyclonal antibody (Biomeda Corp [Foster City, Calif]). Variable expression of GFAP was present in 90% (18/20) and 70% (14/20) of pleomorphic adenomas, and in 20% (2/10) and 0% of chordomas, with the use of the two monoclonal preparations (Dakopatts [Glostrup, Denmark] and BioGenex Laboratories [San Ramon, Calif]), respectively. Normal brain tissue and eight astrocytomas were used as "controls" to compare staining intensity and quality between the polyclonal and monoclonal anti-GFAP antibodies. Glial fibrillary acidic protein positivity with the polyclonal antibody was more intense than that with either monoclonal antibody despite similar (congruent) distributions of tumor cell types that were stained in control brain and astrocytoma tissues. The GFAP polyclonal antibody was more frequently immunoreactive than the monoclonal antibodies, particularly in cells that exhibited chondroid differentiation. These findings may have practical application in surgical pathology.