Photo quiz. Protothecosis.
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Fatal Outcome↗
Biomedical subjects
D Thorning
Publications and source records attributed to D Thorning.
Role of the renal cysteine conjugate beta-lyase pathway in inhaled compound A nephrotoxicity in rats.
BACKGROUND: The sevoflurane degradation product compound A is nephrotoxic in rats and undergoes metabolism to glutathione and cysteine S-conjugates, with further metabolism by renal cysteine conjugate beta-lyase to reactive intermediates. Evidence suggests that toxicity is mediated by renal uptake of compound A S-conjugates and metabolism by beta-lyase. Previously, inhibitors of the beta-lyase pathway (aminooxyacetic acid and probenecid) diminished the nephrotoxicity of intraperitoneal compound A. This investigation determined inhibitor effects on the toxicity of inhaled compound A. METHODS: Fischer 344 rats underwent 3 h of nose-only exposure to compound A (0-220 ppm in initial dose-response experiments and 100-109 ppm in subsequent inhibitor experiments). The inhibitors (and targets) were probenecid (renal organic anion transport mediating S-conjugate uptake), acivicin (gamma-glutamyl transferase), aminooxyacetic acid (renal beta-lyase), and aminobenzotriazole (cytochrome P450). Urine was collected for 24 h, and the animals were killed. Nephrotoxicity was assessed by histology and biochemical markers (serum BUN and creatinine; urine volume; and excretion of protein, glucose, and alpha-glutathione-S-transferase, a predominantly proximal tubular cell protein). RESULTS: Compound A caused dose-related proximal tubular cell necrosis, diuresis, proteinuria, glucosuria, and increased alpha-glutathione-S-transferase excretion. The threshold for toxicity was 98-109 ppm (294-327 ppm-h). Probenecid diminished (P < 0.05) compound A-induced glucosuria and excretion of alpha-glutathione-S-transferase and completely prevented necrosis. Aminooxyacetic acid diminished compound A-dependent proteinuria and glucosuria but did not decrease necrosis. Acivicin increased nephrotoxicity of compound A, and aminobenzotriazole had no consistent effect on nephrotoxicity of compound A. CONCLUSIONS: Nephrotoxicity of inhaled compound A in rats was associated with renal uptake of compound A S-conjugates and cysteine conjugates metabolism by renal beta-lyase. Manipulation of the beta-lyase pathway elicited similar results, whether compound A was administered by inhalation or intraperitoneal injection. Route of administration does not apparently influence nephrotoxicity of compound A in rats.
Anesthetics, Inhalation↗
Role of renal cysteine conjugate beta-lyase in the mechanism of compound A nephrotoxicity in rats.
BACKGROUND: The sevoflurane degradation product compound A is nephrotoxic in rats, in which it undergoes extensive metabolism to glutathione and cysteine S-conjugates. The mechanism of compound A nephrotoxicity in rats is unknown. Compound A nephrotoxicity has not been observed in humans. The authors tested the hypothesis that renal uptake of compound A S-conjugates and metabolism by renal cysteine conjugate beta-lyase mediate compound A nephrotoxicity in rats. METHODS: Compound A (0-0.3 mmol/kg in initial dose-response experiments and 0.2 mmol/kg in subsequent inhibitor experiments) was administered to Fischer 344 rats by intraperitoneal injection. Inhibitor experiments consisted of three groups: inhibitor (control), compound A, or inhibitor plus compound A. The inhibitors were probenecid (0.5 mmol/kg, repeated 10 h later), an inhibitor of renal organic anion transport and S-conjugate uptake; acivicin (10 mg/kg and 5 mg/kg 10 h later), an inhibitor of gamma-glutamyl transferase, an enzyme that cleaves glutathione conjugates to cysteine conjugates; and aminooxyacetic acid (0.5 mmol/kg and 0.25 mmol/kg 10 h later), an inhibitor of renal cysteine conjugate beta-lyase. Urine was collected for 24 h and then the animals were killed. Nephrotoxicity was assessed by light microscopic examination and biochemical markers (serum urea nitrogen and creatinine concentration, urine volume and urine excretion of protein, glucose, and alpha-glutathione-S-transferase [alpha GST], a marker of tubular necrosis). RESULTS: Compound A caused dose-related nephrotoxicity, as shown by selective proximal tubular cell necrosis at the corticomedullary junction, diuresis, proteinuria, glucosuria, and increased alpha GST excretion. Probenecid pretreatment significantly (P < 0.05) diminished compound A-induced increases (mean +/- SE) in urine excretion of protein (45.5 +/- 3.8 mg/24 h vs. 25.9 +/- 1.7 mg/24 h), glucose (28.8 +/- 6.2 mg/24 h vs. 10.9 +/- 3.2 mg/24 h), and alpha GST (6.3 +/- 0.8 micrograms/24 h vs. 1.0 +/- 0.2 microgram/24 h) and completely prevented proximal tubular cell necrosis. Aminooxyacetic acid pretreatment significantly diminished compound A-induced increases in urine volume (19.7 +/- 3.5 ml/24 h vs. 9.8 +/- 0.8 ml/24 h), protein excretion (37.2 +/- 2.7 mg/24 h vs. 22.2 +/- 1.8 mg/24 h), and alpha GST excretion (5.8 +/- 1.5 vs. 2.3 micrograms/24 h +/- 0.8 microgram/24 h) but did not significantly alter the histologic pattern of injury. In contrast, acivicin pretreatment increased the compound A-induced histologic and biochemical markers of injury. Compound A-related increases in urine fluoride excretion, reflecting compound A metabolism, were not substantially altered by any of the inhibitor treatments. CONCLUSIONS: Intraperitoneal compound A administration provides a satisfactory model of nephrotoxicity. Aminooxyacetic acid and probenecid significantly diminished histologic and biochemical evidence of compound A nephrotoxicity, whereas acivicin potentiated toxicity. These results suggest that renal uptake of compound A-glutathione or compound A-cysteine conjugates and cysteine conjugates metabolism by renal beta-lyase mediate, in part, compound A nephrotoxicity in rats.
Aminooxyacetic Acid↗
Secondary hyperparathyroidism complicated by parathyromatosis.
Secondary hyperparathyroidism is a common complication of chronic renal disease. Clinical signs and symptoms tend to be severe and often are not controlled with medical measures. When medical therapy fails, parathyroidectomy becomes necessary. Recurrent hyperparathyroidism is not uncommon following surgery. One cause of surgical failure is parathyromatosis, which has been described as multiple nodules of hyperfunctioning parathyroid tissue scattered throughout the lower neck, superior mediastinum, or the arm if autotransplantation has been performed. Five cases of parathyromatosis in patients with chronic renal failure were identified. Clinical characteristics, course, and prognosis of the patients are reported. All patients had evidence of renal osteodystrophy and complained of severe pruritus and bone and/or joint pain. Three of the five patients had evidence of soft tissue calcification, two complained of muscle weakness, two had multiple fractures, and two eventually died of complications resulting from parathyromatosis. In four of five cases, surgical and medical management were ineffective. The patients described illustrate the severe morbidity and mortality associated with the parathyromatosis in the setting of end-stage renal disease. The pathogenesis remains controversial. Although primary prevention appears to be the most effective means of avoiding this complication, it is mandatory that meticulous care be taken during surgical manipulation. If such measures fail, calcium supplementation, calcitriol, and phosphate restriction may be tried.
Adult↗
Multiple plasmacytomas in skin. Harbinger of aggressive B-immunocytic malignancy.
A 55-year-old alcoholic man with chronic atypical mycobacterial lung disease developed multiple plasmacytomas in the skin over a 6-month period. There was no evidence of either multiple myeloma or plasma cell leukemia at the time of diagnosis; however, evidence of multiple myeloma became apparent about 7 months later, and the man died, despite therapy for this condition, about 22 months after the initial diagnosis of his plasma cell disorder. Despite the apparent rarity of this clinical presentation, the available evidence suggests it is a harbinger of a relatively aggressive B-immunocytic malignancy.
Humans↗
Nerve fibers in human myocardial scars.
The relationships between ischemic heart disease, myocardial scars, ventricular nerve fibers, and ventricular arrhythmias have not been established despite considerable evidence suggesting important correlations. We recently described the reactions of nerve fibers in necrotic, healing, and healed rat myocardium. Prompted by these studies and by the lack of similar information for humans, we studied the structural relationships between nerve fibers and human myocardial scars. Hearts were obtained from transplant surgery and autopsy. Nerve fibers were labeled with antibody to S-100 protein. Light and electron microscopy of left ventricular scars revealed (1) fiber densities greater than those in adjacent intact myocardium, (2) fiber aggregates concentrated irregularly along the periphery of lesions, (3) fibers few in number or absent in the deeper aspects of scars, and (4) axonal enlargements containing clear and dense storage granules within the fiber aggregates. Like all other elements of the scars, the nerve fibers appeared to be oriented predominantly in the long axis of myocytes located at the edges of the lesions. Based on our experimental findings in rat hearts, these studies suggest that human myocardial nerve fibers regenerate after necrotizing injuries and that at least some of the resulting scar-associated fibers have structural features differing from those in uninjured myocardium. We suspect that these structural differences might be associated with functional alterations that could affect the triggering of ventricular arrhythmias.
Adult↗
Contractile cells in rat myocardial scar tissue.
In earlier studies of rat myocardial tissue reactions to necrotizing injuries, we observed in the resulting scar tissue a large number of smooth muscle cells unassociated with blood vessels. Since these cells are not normal components of ventricular myocardium, we studied the appearance and fate of all cells with smooth muscle-like features in healing and healed lesions at intervals up to 10 weeks after ischemic or freeze-thaw injuries. Observations were made with light and electron microscopes, using conventional methods and immunostaining methods to detect alpha-smooth muscle actin. In healing and healed lesions, smooth muscle actin was detected histologically in capillary pericytes, myofibroblasts, and both vascular and nonvascular smooth muscle cells. Its association with cytoplasmic microfilaments in nonsarcomeric myocytoskeletal arrangements was confirmed ultrastructurally. The pericytes and myofibroblasts predominated during the earlier hypercellular healing period. The smooth muscle cells appeared near the end of the first week of repair; they were initially located mainly in presumptive vascular structures, identified by residual basal lamina sheaths, but subsequently located mainly in nonvascular locations. After the second week until the end of the study the number of nonvascular smooth muscle cells increased and that of myofibroblasts decreased. The nonvascular smooth muscle cells predominated in the larger mature scars, especially the transmural ones. From these observations, we have concluded that contractile cells other than cardiac myocytes have important roles in myocardial tissue repair, have suggested that their roles are related to the forces of myocardial contractions, and have discussed their possible functions and lineage interrelationships.
Actins↗
Spatial arrangements of microfibrils in myocardial scars: application of antibody to fibrillin.
Acute myocardial infarction kills myocytes; viable and necrotic myocytes disconnect and the ends of the viable cells become anchored to collagen fibers during reparative scar tissue formation. These anchorages have not been examined in detail, although previous studies have shown that microfibrils (MFs) concentrate at the edges of scars and at the tips of normal papillary muscles. We examined the spatial arrangements of MFs at these two sites in human hearts. Light and electron microscopic observations were made on tissue samples oriented in the long axis of myocytes and stained with monoclonal antibodies to fibrillin, a glycoprotein component of human microfibrils. MFs had identical arrangements at both sites, where they formed fibrous connections between myofibers and collagen fibers. These connections were oriented in the long axis of the muscle cells. At the myocyte ends, MFs appeared to intertwine with MFs in the normal endomysium; in the main body of the connections, MFs formed compact, 200 to 500 nm thick, fibrillin-positive fibers; and at the collagen ends, MFs splayed out among collagen fibrils. These observations indicate that MFs form myofiber-collagen fiber linkages at sites where the power of myocardial contraction is being transmitted to the extracellular connective tissue framework. Formation of such linkages seems to be an important step in the successful repair of necrotic myocardial lesions.
Adult↗
Coumadin-induced gastrointestinal hemorrhage associated with an ileal duplication.
A 31-year-old man had recurrent gastrointestinal hemorrhage after aortic valve replacement and initiation of anticoagulation therapy with coumadin. Radionuclide bleeding scan and subsequent contrast angiogram demonstrated a site of hemorrhage in the distal ileum, and at surgery a 1.8-cm spherical duplication was found. On histologic examination, the duplication was lined with normal ileal mucosa, and near the mouth of the duplication an inflammatory ulceration proved to be the site of hemorrhage. In a young patient with anticoagulation-associated gastrointestinal hemorrhage, alimentary tract duplication should be considered.
Adult↗
Fate of nerve fibers in necrotic, healing, and healed rat myocardium.
Myocardial infarction, myocardial scar tissue formation, and cardiac arrhythmogenesis seem to be associated. There are electrophysiological data suggesting that myocardial nerves are involved in arrhythmia development; however, there are no morphologic studies describing the fate of these nerves following necrotizing myocardial injuries. To describe the reactions of Schwann cells and axons following such injuries, we induced lesions in rat hearts with ischemia or transdiaphragmatic freeze-thawing and examined the acutely necrotic, healing, and healed lesions with light and electron microscopy. Antibodies to Schwann cell-associated S-100 protein were used to facilitate histologic detection. Both forms of injury produced focal lesions in which Schwann cells were killed and axonal segments destroyed; however, the basal lamina sheaths of cardiac myocytes and capillaries, and probably also of nerve fibers, remained largely intact. During 4 weeks of sequential observations, Schwann cells and axons were components of a hypercellular healing front that began at the periphery and moved toward the center of each lesion. Their proliferation and growth may have occurred within the original nerve basal lamina sheaths, and reparative axonal enlargements contained an abundance of 50- to 100-nm clear and dense storage granules. Fully developed nerve fibers were not only present in newly formed scar tissue but also appeared to be present in significantly greater density than in uninjured myocardial tissue. These findings demonstrate that proliferative nerve fiber regeneration occurs from the edges of necrotizing myocardial injuries, that healing results in relatively large number of nerve fibers in newly formed scars, and that axons in these scar-associated nerve fibers contain an abundance of neurosecretory granules. The functional significance of these observations remains to be determined.
Animals↗
Connective tissue cells in healing rat myocardium. A study of cell reactions in rhythmically contracting environment.
To better understand the tendency of myocardium to heal by scarring rather than regeneration, the authors examined the responses of connective tissue cells (CTCs) after three types of necrotizing injuries. Derived from myocardial interstitial cells, CTCs proliferated in both the connective tissue space and the compartment of necrotic myocytes. They assumed various cell forms: fibrocytelike CTCs throughout the sites of injury deposited extracellular scar tissue elements, established CTC-myocyte contacts, and helped anchor myocytes to scar tissue with myotendonlike specializations; CTCs with more complex forms established CTC-myocyte relationships, suggesting important roles in communication and tissue remodeling. CTCs within scar tissue differentiated into myofibrocytes, chondrocytes, and possibly smooth muscle cells. Most scar tissue elements were disposed in the long axis of myocytes. These alterations in form indicate that CTCs have various roles in myocardial repair and suggest that a number of the roles are modulated by contractile forces.
Animals↗
Basal lamina of rat myocardium. Its fate after death of cardiac myocytes.
As part of a study of the interactions between myocardial cells and extracellular matrix during healing of necrotic lesions, we have examined the fate of myocyte basal lamina (BL) after injury with ischemia, freeze-thawing, or isoproterenol. Using light and electron microscopy, and antibodies to three BL-associated antigens, we found that the BL of necrotic myocytes remained largely intact and continued to delineate the myocyte compartment from connective tissue space. Inflammatory cells entered the myocyte compartment through holes in the acellular BL and removed cell debris. The holes may have been produced by inflammatory cells and/or by the stretching force of the beating heart. After removal of debris, some BL sheaths of necrotic myocytes collapsed, resulting in spatial approximation of vessels. Interstitial cells deposited collagen and elastic fibers in the connective tissue space and within portions of the myocyte compartment. The acellular myocyte BL, collapsed or not, retained normal antigen staining for type IV collagen, laminin, and heparan sulfate for about 10 days, then showed diminished staining in patchy areas. These areas may correspond to BL disruption and degradation in conjunction with fibrosis, although a substantial amount of acellular BL remained in situ and became embedded in scar tissue. At least two types of granulo-vesicular bodies, measuring 25 to 60 and 60 to 160 nm respectively, were associated with the acellular BL; these were of unknown origin and function. The study shows that the fate of acellular BL in injured myocardium is similar to the fate of BL in other injured tissues; however, the appearance of holes in acellular BL, within hours after injury, is unusual and may enhance scar tissue formation. Whether the acellular BL contributes to regeneration of myocardium, as do acellular BLs in other injured tissues, remains to be determined.
Animals↗
Myocyte reactions at the borders of injured and healing rat myocardium.
To better understand the apparent tendency of myocardium to heal by scarring rather than by restoration of normal structure, we have examined by light and electron microscopy the basic reactions of rat ventricular myocytes and their interactions with the extracellular matrix. Using three different types of necrotizing injuries, we found that necrotic myocytes separated from viable myocytes at intercalated discs leaving blunt-ended stumps at the edge of each lesion; the basal lamina of necrotic myocytes remained largely intact and spanned the gap between viable myocytes on opposite sides of each lesion. A small number of stumps were capped off by a new layer of basal lamina and showed no evidence of proliferative activity. The majority of the stumps developed cell processes that extended along the acellular myocyte basal lamina sheaths. These processes had one of two different fates. Some became apposed to similar processes, formed intercalated disc attachments, increased myofibrillar mass, and appeared to be associated with muscle reconstruction. Others developed elongate tapered ends, which terminated in myotendinous connections to scar tissue. The outcome of healing necrotic myocardium, like the healing of noncardiac necrotic tissue injuries, appears to be a function of cell growth and extracellular framework guidance; however, unlike healing of noncardiac tissues, healing of myocardium is uniquely complicated by continuing muscle contractions. We think the rhythmic pulling at the edges of necrotic lesions induces formation of myotendinous attachments, which anchor myocytes to scar tissue and probably prevent further growth.
Animals↗
Epithelial denudement in the gastrointestinal tracts of two bone marrow transplant recipients.
Examination of autopsy specimens from two patients revealed extensive denudement of gastrointestinal (GI) tract epithelium but preservation of basic mucosal structure otherwise. Each patient had received an allogeneic bone marrow transplant for acute leukemia. Although both patients experienced transient episodes of graft-versus-host disease (GVHD), neither experienced significant GI tract symptomatology. The usual explanations for GI epithelial denudement in such patients focus on the mechanisms of accelerated epithelial cell loss. Also considered in these two patients was the possibility that previous treatment(s) had severely interfered with the capacity for epithelial cell renewal. Chemotherapy, total body irradiation, or GVHD, alone or in some combination, may have depleted the stem cell populations and interfered with proliferative epithelial repair.
Acute Disease↗
Freeze-thaw injury of rat heart across an intact diaphragm: a new model for the study of the response of myocardium to injury.
A new method for producing a circumscribed injury in rat myocardium is described. It utilises laparotomy and freeze-thawing across an intact diaphragm. Morbidity and mortality are negligible because the chest and pericardial cavities, the major coronary vessels, and the major branches of the conduction system remain intact. The size and location of the injury are reproducible and its sharp delineation facilitates accurate collection of samples from areas of interest. The myocytes are killed in the area of injury, whereas the capillary, nerve and connective tissue cells are killed centrally but preserved peripherally in a perimeter zone of injury in which capillaries remain patent. The reparative activities are initiated at the border between injured and uninjured myocardium; as they progress over the ensuing 6 weeks, the volume of damaged myocardium diminishes rapidly leaving only a rim of subepicardial scar tissue, and the thickness of ventricular muscle between the scar and endocardium returns almost completely to its pre-injury width. The mechanisms involved in the repair process are being investigated.
Animals↗
Long-term survival in small-cell carcinoma of the lung: a population experience.
Small-cell lung carcinoma (SCLC) is a rapidly progressive and fatal disease. Historically, surgical resection or radiotherapy of the primary tumor has done little to prolong survival, although the use of combination chemotherapy is more effective. Reported here is the survival experience of 1,538 incident cases of SCLC identified through the Surveillance, Epidemiology and End Results Program in western Washington State from 1974 to 1982. The survival experience of this population series is similar to that reported from specialized referral centers. For 71 of 78 persons surviving at least 24 months, the original diagnostic slides were independently reviewed, 47 cases being confirmed as SCLC. No differences were found in actuarial survival estimates between those confirmed and those not confirmed as SCLC. Multivariate survival analysis was conducted to estimate the effects on survival of stage, therapy, age, sex, primary site, and histologic type. All factors except primary site and histologic type significantly influence initial survival rates. However, the only factor related to post--two-year (ie, long-term) survival, once stage is accounted for, is whether surgery was received as a first course of therapy. Those not receiving surgery were at four times the risk of death as those who did. These results indicate that long-term survival can be achieved in patients with SCLC treated in the community, and that the chance of surviving an additional two years for such patients is approximately 40%.
Adult↗
Bronchiolitis obliterans caused by Legionella pneumophila.
A diabetic patient presented with symptoms and laboratory findings compatible with atypical pneumonia. Despite appropriate antibiotic therapy, his dyspnea, arterial oxygenation, and chest roentgenographic findings worsened. Because the patient had a history of homosexual contact, an open lung biopsy was obtained to morphologically define the tissue reaction and to search for a specific etiology. Histologic examination showed bronchiolitis obliterans but did not demonstrate a cause. Legionnaires' disease was subsequently diagnosed on the basis of a fourfold rise in indirect fluorescent antibody titer. This case report demonstrates that Legionella pneumophila may induce lung injury with bronchiolitis obliterans. Such patients may benefit from corticosteroid treatment.
Biopsy↗
Human megakaryocytic progenitors (CFU-M) assayed in methylcellulose: physical characteristics and requirements for growth.
The basic culture requirements and several physical characteristics were defined for megakaryocytic colony-forming cells (CFU-M) from normal human marrow growing in methylcellulose. Ficoll-hypaque separated mononuclear cells from human marrow gave rise to megakaryocytic colonies in the presence of normal human plasma and phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM). Their identity as megakaryocytic colonies was confirmed by immunofluorescence staining with a monoclonal antibody to human factor VIII antigen and by electron microscopy of individually harvested colonies. Demonstration of the single-cell origin of the colonies was provided by analysis of the glucose-6-phosphate dehydrogenase (G-6-PD) enzyme type of individually harvested colonies grown from a G-6-PD heterozygote. The colonies grew best in heparinized or citrated plasma as opposed to serum. Detailed studies suggested that platelet-release products were responsible for this difference. Tritiated thymidine suicide studies showed that the percentage of CFU-M in DNA synthesis was 23 +/- 8% (n = 10). The modal velocity sedimentation rate of CFU-M was 4.9 +/- 0.6 mm/hr (n = 4) while that of concurrently studied granulocyte/macrophage colony-forming cells (CFU-GM) was 5.7 +/- 0.5 mm/hr. Examination of the PHA-LCM dose-response characteristics suggested the presence in the conditioned medium of an inhibitor to megakaryocyte colony growth which was partially removed by chromatography of the medium on Sephadex G-100. The resulting conditioned medium increased the cloning efficiency for CFU-M compared with that with crude PHA-LCM (15.3 +/- 7.0 and 8.2 +/- 5.3/10(5) marrow cells, respectively).
Blood↗