The PGC-1/ERR signaling axis in cancer.

Proliferating cells need to produce a large amount of energy and, at the same time, need to maintain a constant supply of biosynthetic precursors of macromolecules that are used as building blocks for generating new cells. Indeed, many cancer cells undergo a switch from mitochondrial to glycolytic metabolism and display a truncated tricarboxylic acid cycle to match these specific metabolic requirements of proliferation. Understanding the mechanisms by which cancer cells reprogram various metabolic pathways to satisfy their unique bioenergetic requirements has become an active field of research. Concomitantly, it has emerged that members of a family of orphan nuclear receptors known as the estrogen-related receptors (ERRs), working in concert with members of the PPARγ coactivator (PGC)-1 family, act as central transcriptional regulators of metabolic gene networks involved in maintaining energy homeostasis in normal cells. Recent studies have suggested that the PGC-1/ERR transcriptional axis is also important in the metabolic reprogramming of cancer cells. This review focuses on the functional integration of the PGC-1/ERR axis with known oncogenes and the observation that modulation of the activity of this axis can have both pro- and anti-proliferative properties.

A cluster of transfusion-associated babesiosis in extremely low birthweight premature infants.

Babesiosis is a parasitic infection of the red blood cells most often acquired by a tick bite. As it has also been known to be transmitted vertically and via transfusion, neonates have occasionally been reported with the infection. Here, we report a series of three premature neonates who acquired babesiosis via blood transfusion from a single donor, one of whom had difficulty clearing the infection and required multiple antimicrobials.

Estrogen-related receptor α, the molecular clock, and transcriptional control of metabolic outputs.

Metabolism and circadian rhythms must be closely integrated to support the energetic needs of the organism linked to the daily timing of physiological and behavioral processes. Although components of the molecular clock can directly target some metabolic genes, the control of metabolic clock output is believed to be mediated mostly through the action of transcription factors whose patterns of expression are rhythmic in metabolic tissues. Our recent work has identified the orphan nuclear receptor estrogen-related receptor α (ERRα), a potent effector of metabolic gene networks, as a direct regulator of the molecular clock. Thus, by acting both upstream of and downstream from the molecular clock, ERRα serves as a key transcription factor linking the clock with metabolic control.

Unusual biclonal plasma cell dyscrasia with crystallike inclusions producing colonic tumors (plasma cell polyposis) and terminating in T-cell lymphoma.

A 62-year-old man underwent a partial colectomy for persistent rectal bleeding. Multiple submucosal lesions up to 7 cm in diameter were identified and were composed of plasmacytoid and histiocytoid cells with crystallike inclusions. Ultrastructurally, inclusions were bounded by rough endoplasmic reticulum. Immunohistochemical studies demonstrated a monoclonal population of IgA kappa-positive plasma cells. Immunofixation using a saline extract of the tumor revealed two distinct bands: one for IgG kappa and another for IgA kappa. Southern blotting revealed a germline configuration for the immunoglobulin heavy-chain gene and the T-cell antigen receptor beta-chain gene. A bone marrow aspirate contained 12% plasma cells, some of which had cytoplasmic inclusions. Eight months after surgery, the patient developed a large mediastinal mass. Histologic and immunohistochemical studies indicated that this mass was an undifferentiated neoplasm. However, gene rearrangement studies indicated a T-cell lymphoma. This patient illustrates a rare association between a plasma cell neoplasm and a T-cell lymphoma.

Small lymphocytic pulmonary lymphoma. Diagnosis by transthoracic fine needle aspiration.

A 77-year-old woman was found to have multiple densities on chest roentgenogram. Exfoliative cytology, bronchoscopy with brushings and washings, and transbronchial biopsy revealed a monomorphic population of small lymphocytes suggestive of lymphoma. Transthoracic fine-needle aspiration was performed to provide additional material for immunologic marker study. Immunocytochemistry revealed a monoclonal population of B-cells, which confirmed a diagnosis of small lymphocytic lymphoma. Chemotherapy resulted in significant clinical and roentgenographic improvement.

Computed tomography of benign mesenchymoma of the neck.

Mesenchymoma is a tumor composed of two or more mesenchymal components along with fibrous tissue. We describe the CT findings in a case of benign mesenchymoma that presented as an unusual neck mass in an elderly woman.

Hemispherical spondylosclerosis: MR appearance.

We present a case of hemispherical spondylosclerosis (HSS) in a middle-aged woman with low back pain. The plain radiographic findings, CT and MR appearance, and pathological examination are described, and the difficulties encountered in differentiating HSS from malignancy and infection are discussed.

Cardiorespiratory and cellular changes with interleukin 2 infusion in sheep.

Recombinant interleukin 2 (rIL-2) administration, a new form of therapy for patients with far-advanced cancer, is associated with a "third space" syndrome, i.e., pulmonary edema, respiratory distress, and hypoxemia, which limits the dose and duration of treatment. To extend our knowledge regarding this toxicity, we established a sheep chronic lung lymph fistula model and measured hemodynamics, arterial blood gases, caudal mediastinal (lung) lymph flow (QL), and blood and lung lymph cellular changes before, during, and after (recovery) a 3-day continuous rIL-2 infusion (9 x 10(5) U/kg). Moderate systemic hypotension, mild pulmonary hypertension, and an increase in alveolar-arterial PO2 gradient was present on day 3 of rIL-2 infusion. QL increased from a base line of 1.9 +/- 0.2 to a maximum of 4.3 +/- 1.1 ml/15 min on day 3 of rIL-2 infusion. At no time was there a change in lymph-to-plasma protein ratio. The leukocyte count increased significantly to 16.1 +/- 4.5 x 10(3) cells/mm3 at recovery day 1. The percentage of blood lymphocytes decreased significantly by day 1 of rIL-2 infusion, returned to base-line levels on day 3, and significantly increased on day 2 of recovery. Lung lymph lymphocytes decreased significantly on days 1 and 2 of rIL-2 infusion. There was a shift in their size; i.e., their area increased from 32 +/- 7 to 57 +/- 19 micron 2 (P less than 0.05) by day 2 of rIL-2 infusion. By day 1 of recovery, lung lymph lymphocyte counts increased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiopulmonary toxicity of adoptive immunotherapy.

Adoptive immunotherapy, the administration of interleukin-2 (IL-2) and interleukin-2 activated cells, leads to tumor regression in some patients with advanced cancer. Although this new therapeutic modality offers hope for the future, at present, a multitude of toxicities limit the total dose and duration of therapy. Among the toxic side effects a purported third space or vascular leak syndrome is the most serious. In this review, we detail the evidence for a third space syndrome (peripheral edema, ascites, oliguria, elevated serum creatinine levels) and cardiopulmonary dysfunction (hypotension, respiratory distress, pulmonary edema, hypoxemia) with adoptive immunotherapy in human and animal studies. We conclude that IL-2 administration is associated with increased pulmonary microvascular permeability, infiltration of the lung parenchyma with large esterase negative lymphoid cells, hypoxemia, systemic hypotension, positive fluid balance and, in animals, transient pulmonary hypertension. These abnormalities do not seem to be caused by IL-2 directly; the causes may be mediated by IL-2 activated lymphocytes or other IL-2 activated cellular mediators.

A comparison of the cardiopulmonary effects of continuous versus bolus infusion of recombinant interleukin-2 in sheep.

The systemic administration of recombinant interleukin-2 (rIL-2) is used for the treatment of patients with far advanced cancer. However, treatment may be limited by a so-called "third space" syndrome. Whether these side effects are due to the total dose used or the method of administration is unclear. To define whether the continuous (Group 2) or bolus (Group 3) i.v. infusion of 9 x 10(5) units/kg rIL-2 over 72 h is associated with similar toxicities, we established a chronic sheep model and monitored changes in systemic and pulmonary vascular pressures, cardiac function, and gas exchange. At 72 h lung lymph flow, lymph/plasma protein ratios, lung histology, and extravascular lung water/dry lung weight were obtained. In both groups the infusion of rIL-2 resulted in an increase in high protein lung lymph flow, an increase in cardiac output, and a decrease in systemic vascular resistance. Large lymphoid cells were found by histology to be infiltrating the lung interstitium. In Group 2, in addition, there were mild pulmonary hypertension [pulmonary artery pressures increased from 14 +/- 5 to 22 +/- 6 mmHg (P less than 0.05)], systemic hypotension [81 +/- 7 compared to a baseline of 95 +/- 9 mmHg (P less than 0.01)], and worsening gas exchange. We conclude that a 72-h continuous or bolus infusion of equivalent doses of rIL-2 are associated with cardiopulmonary toxicity; however, pulmonary hypertension, systemic hypotension, and gas exchange are worse in animals receiving the continuous infusion.

Cardiopulmonary effects of recombinant interleukin-2 infusion in sheep.

The systemic administration of recombinant interleukin-2 (rIL-2) with or without lymphokine-activated killer (LAK) cells, a new treatment for patients with advanced cancer, is associated with a presumed "third-space" syndrome. To further define the extent and time course of this toxicity, we established a chronic sheep model and monitored changes in systemic and central vascular pressures, cardiac function, and gas exchange during a 72-h continuous intravenous infusion of rIL-2 at a total dose of 5 (group 3) or 9 x 10(5) U/kg (group 4). At 72 h, caudal mediastinal lymph flow, histology, and extravascular lung water-to-dry lung weight ratio (EVLW/DLW) were obtained. During the rIL-2 infusion there was a dose-dependent significant decrease in systemic blood pressure and arterial Po2 and an increase in core temperature. In group 4, pulmonary arterial pressure increased from a base line of 13 +/- 5 to 21 +/- 6 mmHg (P less than 0.05). Lung lymph flow was significantly increased in groups 3 and 4 compared with animals receiving 0.9% NaCl or excipient infusions (groups 1 and 2). EVLW/DLW values were elevated in groups 3 and 4 (P less than 0.01). In animals receiving rIL-2, histological evaluation revealed a dose-dependent infiltration of lung tissue by lymphoblastoid cells that stained esterase negative. We conclude that rIL-2 infusion in doses comparable to those given to humans results in alterations in systemic and central hemodynamics, gas exchange, high-protein lung lymph flow, and infiltration of lymphoblastoid cells into the lung parenchyma.

Effects of protamine, heparinase, and hyaluronidase on endothelial permeability and surface charge.

We undertook studies in the isolated perfused rat lung to determine 1) the effects of endothelial charge neutralization with the polycation protamine sulfate on microvascular permeability, lung water, and anionic ferritin binding to the endothelium and 2) the role of heparan sulfate and hyaluronate, negatively charged cell surface glycosaminoglycans, on permeability. Capillary permeability was determined by tissue 125I-albumin accumulation in isolated perfused rat lungs. In control lungs the 5-min albumin uptake was 0.50 +/- 0.05 cm3.s-1.g dry tissue-1 X 10(-3). It was increased by 132 +/- 7.8% (P less than 0.001) by protamine (0.08 mg/ml) and 65 +/- 12% (P less than 0.01) by heparinase (5 U/ml), whereas hyaluronidase (25 NFU/ml) was without effect. In control lungs total water was 4.83 +/- 0.15 ml g/dry tissue. Protamine increased lung water 12 +/- 2% (P less than 0.05). Heparinase caused a 9 +/- 3% increase (P less than 0.05), and hyaluronidase had no effect. Electron microscopy demonstrated that protamine increased anionic ferritin binding to the surface of endothelial cells. We conclude that protamine sulfate neutralization of negative charge in the pulmonary microcirculation leads to increased microvascular permeability. Heparin sulfate may be responsible for this charge effect.

Deficiency of the tryptase-positive, chymase-negative mast cell type in gastrointestinal mucosa of patients with defective T lymphocyte function.

The distribution and concentration of human T (tryptase-positive, chymase-negative) and TC (tryptase-positive, chymase-positive) mast cells were examined in Carnoy's-fixed specimens of the gastrointestinal tract of normal individuals, patients with inflammatory bowel diseases, and patients with immunodeficiency disorders. In normal specimens, T mast cells predominated in the mucosa (89%), with a mean concentration of 17,850 +/- 4,998 per mm3 (+/- SD, n = 16), whereas TC mast cells predominated in the submucosa (90%) with a mean concentration of 7,516 +/- 1,227 per mm3 (+/- SD, n = 16). The concentrations of T and TC mast cells in specimens of ileum from five patients with active Crohn's disease and of colon from three patients with active ulcerative colitis were not significantly different (p greater than 0.4) from normal values. Three patients with combined immunodeficiency disorders demonstrated a marked decrease in the concentration of the T mast cells in the intestinal mucosa, to 540 +/- 630, and a corresponding decrease in the percentage of T mast cells to 9%. Concentrations of TC mast cells were unchanged, both in the mucosa and in the submucosa. In three patients with acquired immunodeficiency syndrome, a similar deficiency of the T mast cell type was observed in the ileal mucosa, with a mean concentration of 788 +/- 534 T mast cells per mm3, but not in the appendiceal and colonic mucosa of one of the three patients. These findings indicate a role for functional T lymphocytes in the development of the T mast cell type in humans, and suggest divergent pathways for development of T and TC mast cells.

Fatal pulmonary fibrosis from low-dose bleomycin therapy.

Six weeks after receiving a total dose of 20 units of bleomycin sulfate as part of BACOP therapy for non-Hodgkin's lymphoma, our patient had dyspnea and cough with marked hypoxemia. Open lung biopsy established the diagnosis of "bleomycin lung," confirmed by postmortem examination. Fatal bleomycin pulmonary toxicity can develop with any dosage, and routine tests are incapable of detecting early, reversible toxicity.

Mast cells in human keloid, small intestine, and lung by an immunoperoxidase technique using a murine monoclonal antibody against tryptase.

A murine monoclonal antibody (G5) against human lung mast cell tryptase was used for selective staining of human mast cells by an indirect immunoperoxidase method. Human tissues (keloid, small bowel, lung) were fixed in either Carnoy's fluid or neutral buffered formalin. In all three tissues the number and location of G5-stained mast cells corresponded closely with metachromatic toluidine blue-stained mast cells, although the immunospecific technique appeared to be more sensitive. In lung the average concentration of G5-positive mast cells after Carnoy's fixation was 15,695/cu mm of subepithelial tissue in bronchi and bronchioles and 26,580/cu mm of alveolar wall, in small bowel was 20,958/cu mm of mucosa and 8576/cu mm of submucosa, and in keloid was 3068/cu mm. Formalin fixation significantly reduced concentrations of G5-positive mast cells in all tissues except keloid.

Two types of human mast cells that have distinct neutral protease compositions.

Two human mast cell types were identified by immunohistochemical techniques in skin, lung, and small intestine. One type contains the neutral proteases, tryptase and chymotryptic proteinase, and is termed the TC mast cell. The second type contains only tryptase and is termed the T mast cell. Both types are fixed better by Carnoy's fluid than by formalin. The percentage of mast cells accounted for by the T type was 12 in skin; 98 in mucosa and 13 in submucosa of small intestine; and 77 in bronchial/bronchiolar subepithelium, about 97 in bronchial/bronchiolar epithelium, and 93 in alveoli of lung. Dispersed lung cells contained 90% T mast cells. The mean area of TC mast cells (76 micron2) was slightly larger than that of T mast cells (66 micron2); however, there was such extensive overlap that individual mast cells belonging to different types could not be distinguished on the basis of size. The recognition of human mast cell types with distinct protease compositions suggests a higher level of complexity of human mast cell-mediated reactions than heretofore appreciated.

Microtubular aggregates within rough endoplasmic reticulum: an unusual ultrastructural feature of extraskeletal myxoid chondrosarcoma.

Two extraskeletal myxoid chondrosarcomas were examined by electron microscopy. In addition to the well-described ultrastructural features indicative of chondroblastic origin, both of these chondrosarcomas had unusual parallel microtubules packed within rough endoplasmic reticulum. This paper reviews the differential diagnosis of extraskeletal myxoid chondrosarcoma and discusses ultrastructural examination as a valuable adjunct in the diagnosis of this uncommon soft tissue tumor.

Adrenal myelolipoma diagnosis by computed-tomography-guided fine-needle aspiration. A case report.

A case of adrenal myelolipoma, to the authors' knowledge, the first diagnosed by fine-needle aspiration, is reported. Adrenal myelolipoma is an unusual, benign lesion with a distinctive cytologic appearance. Computed tomography (CT)-guided fine-needle aspiration of the adrenal gland involves minimal morbidity and provides rapid, reliable differentiation of this entity from a malignant neoplasm.

Cerebral fat embolism following cardiac surgery.

We describe 3 cases of cerebral fat embolism associated with cardiac surgery. The autopsy findings suggested that in 2 cases, the embolic fat globules entered the systemic circulation directly as a result of protrusion of epicardial fat into the left atrial chamber along the suture line in one case, and through an atrial septal defect in the other. The characteristic latent interval between surgical trauma and onset of neurologic manifestations was lacking in both cases. The evolution of neurologic manifestations and the pathologic findings in the third case were similar to those usually seen in posttraumatic fat embolism. This study suggests that the pathogenetic mechanisms of cerebral fat embolism following cardiac surgery may vary in different cases. Also, it emphasizes the importance of autopsy in the investigation of this serious but preventable complication.