The effect of walking poles on the knee adduction moment in patients with varus gonarthrosis.

OBJECTIVES: (1) Test the hypothesis that walking poles decrease the external knee adduction moment during gait in patients with varus gonarthrosis, and (2) explore potential mechanisms. DESIGN: Thirty-four patients with medial compartment knee osteoarthritis (OA) and varus alignment underwent three dimensional (3D) gait analysis with and without using walking poles. Conditions were randomized and walking speed was maintained ±5% of the self-selected speed of the initial condition. The pole held in the hand of the unaffected side was instrumented with a compression load cell. RESULTS: Student's t tests for paired samples indicated small but statistically significant increases (P < 0.001) in knee adduction moment (calculated from inverse dynamics) for its first peak, second peak and angular impulse when using the poles; mean increases (95% confidence interval - CI) were 0.17%BW*Ht (0.08, 0.27), 0.17%BW*Ht (0.04, 0.30) and 0.15%BW*Ht*s (0.09, 0.22), respectively. There was a decrease (P = 0.015) in vertical ground reaction force (-0.02 BW (-0.04, -0.01)), yet increase (P < 0.001) in its frontal plane lever arm about the knee (0.30 cm (0.15, 0.44)), at the time of the first peak knee adduction moment. Pole force in the vertical direction was inversely related (r = -0.34, P = 0.05) to the increase in first peak adduction moment. CONCLUSION: Although results are variable among patients, and may be related to individual technique, these overall findings suggest that walking poles do not decrease knee adduction moments, and therefore likely do not decrease medial compartment loads, in patients with varus gonarthrosis. Decreases in knee joint loading should not be used as rationale for walking pole use in these patients.

Endocan or endothelial cell specific molecule-1 (ESM-1): a potential novel endothelial cell marker and a new target for cancer therapy.

Endocan, previously called endothelial cell specific molecule-1, is a soluble proteoglycan of 50 kDa, constituted of a mature polypeptide of 165 amino acids and a single dermatan sulphate chain covalently linked to the serine residue at position 137. This dermatan sulphate proteoglycan, which is expressed by the vascular endothelium, has been found freely circulating in the bloodstream of healthy subjects. Experimental evidence is accumulating that implicates endocan as a key player in the regulation of major processes such as cell adhesion, in inflammatory disorders and tumor progression. Inflammatory cytokines such as TNF-alpha, and pro-angiogenic growth factors such as VEGF, FGF-2 and HGF/SF, strongly increased the expression, synthesis or the secretion of endocan by human endothelial cells. Endocan is clearly overexpressed in human tumors, with elevated serum levels being observed in late-stage lung cancer patients, as measured by enzyme-linked immunoassay, and with its overexpression in experimental tumors being evident by immunohistochemistry. Recently, the mRNA levels of endocan have also been recognized as being one of the most significant molecular signatures of a bad prognosis in several types of cancer including lung cancer. Overexpression of this dermatan sulphate proteoglycan has also been shown to be directly involved in tumor progression as observed in mouse models of human tumor xenografts. Collectively, these results suggest that endocan could be a biomarker for both inflammatory disorders and tumor progression as well as a validated therapeutic target in cancer. On the basis of the recent successes of immunotherapeutic approaches in cancer, the preclinical data on endocan suggests that an antibody raised against the protein core of endocan could be a promising cancer therapy.

Increase of rat pulmonary microvascular permeability to albumin by recombinant interleukin-2.

Immunotherapy with the lymphokine interleukin-2 (IL-2), with or without lymphokine activated killer (LAK) cells, offers a new approach to the treatment of solid tumors. Unfortunately, most patients receiving IL-2 and LAK cells develop a "third space syndrome" from a presumed generalized increase of vascular permeability. We have investigated the role of IL-2 on lung fluid balance, by measuring changes in lung water and albumin intake. Rats were injected with IL-2 500,000 U i.p. three times a day for 1 to 4 days. At the completion of the injections, lungs were isolated and perfused, and total lung water (TLW) and 125I-albumin uptake were measured. After 1 day of injections, TLW increased from 4.90 +/- 0.14 to 5.57 +/- 0.34 ml/g dry lung and albumin uptake nearly doubled from 0.47 +/- 0.08 to 0.91 +/- 0.28 cm3/s/g dry lung X 10(-3). Longer injection periods increased both TLW and albumin uptake further. After 2 days, TLW and albumin uptake were also significantly increased by 160,000 U i.p. three times a day, but not by 40,000 or 10,000 U. To eliminate possible contributions to increased permeability by (a) LAK cells generated in vivo, or (b) circulating leukocytes, we isolated lungs from normal rats and perfused them for 5 min with a cell-free perfusate containing IL-2 (2, 10, or 5 X 10(-3) U/ml) excipient or 0.9% NaCl placebo. TLW was similar in all groups, but albumin uptake was significantly increased by 10,000 and 50,000 U/ml (0.94 +/- 0.15 and 0.82 +/- 0.16 cm3/s/g dry lung X 10(-3), respectively), but not by 2,000 U/ml. We conclude that lung microvascular albumin permeability is increased following administration of IL-2 in vivo and in vitro. We suggest that LAK cells are not required for the initiation of increased permeability and that IL-2 may have some direct effect on the pulmonary microvasculature.

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.

Inhibition of protein tyrosine phosphatases blocks calcium-induced activation of metaphase II-arrested oocytes of Xenopus laevis.

We have studied the effect of a protein tyrosine phosphatases (PTP) inhibitor on calcium-induced activation of Xenopus laevis oocytes arrested at metaphase II. Ammonium molybdate microinjection blocked pronucleus formation following A23187 treatment while cortical granules still underwent exocytosis. Pronuclei still occurred in ammonium molybdate-injected oocytes following 6-DMAP addition. Changes that usually occurred following A23187 exposure were inhibited in the presence of ammonium molybdate in the oocyte: MAPK dephosphorylation, p34(cdc2) rephosphorylation and cyclin B2 and p39(mos) proteolysis. These results suggest that a PTP is involved in the activation of the ubiquitin-dependent degradation machinery.

In vivo interleukin-2 activated sheep lung lymph lymphocytes increase ovine vascular endothelial permeability by non-lytic mechanisms.

Therapeutic doses of recombinant interleukin-2 (rIL-2) often result in systemic toxicity consistent with increased vascular permeability. rIL-2 activated lymphocytes (IALs) may produce endothelial dysfunction and have cytolytic potential. However, much of the data on IAL cytotoxicity comes from the use of in vitro activated IALs. Alternatively, rIL-2 may enhance permeability directly or via release of various cytokines by host effector cells. The cytotoxicity of in vivo activated lung lymph lymphocytes has been studied in an ovine model of rIL-2 toxicity. The in vivo IALs had no significant endothelial cytolysis at effector to target ratios of 100:1. However, the in vivo IALs increased endothelial monolayer permeability to albumin, dependent on the concentration of IALs. rIL-2 induced no endothelial cytolysis or permeability alterations at doses of 10(5) and 2 x 10(5) U/ml, respectively. These findings suggest that the acute endothelial dysfunction characteristic of the vascular leak syndrome is not due to rIL-2 directly, but is mediated by in vivo IALs via non-cytolytic mechanisms and/or the release of secondary cytokines in response to rIL-2.

Comparative evaluation of cefmenoxime versus cefoxitin in serious infections.

Fifty-nine patients with serious infections were assigned at random in a two-to-one ratio to receive either cefmenoxime or cefoxitin given intravenously in a dosage of 0.5 to 2.0 g every six hours. Of 44 patients evaluable for efficacy, eight had concomitant bacteremia and all but 10 had serious underlying disease. The average duration of therapy was seven days. All patients with skin and soft tissue infections were cured after treatment with either antibiotic. Cefmenoxime achieved clinical and bacteriologic cures in 92 and 83 percent, respectively, of 12 patients with pneumonia and in 100 and 82 percent of 11 patients with urinary tract infections. Cefoxitin therapy resulted in clinical and bacteriologic cures in all four patients with pneumonia. Among 10 patients with urinary tract infection, respective cure rates were 90 and 50 percent. Both antibiotics were well tolerated. One cefmenoxime-treated patient discontinued treatment because of a rash.

Release of endothelin in relation to tumor necrosis factor-alpha in porcine Pseudomonas aeruginosa-induced septic shock.

Septic shock is characterized by surges of tumor necrosis factor-alpha (TNF-alpha) along with myocardial dysfunction and systemic hypotension. TNF-alpha promotes the release of immunoreactive endothelin (ET). Because TNF-alpha is elevated in septic shock, we hypothesized that elevated levels of endothelin can contribute to cardiac dysfunction and hypotension. We infused live Pseudomonas aeruginosa into anesthetized, hemodynamically monitored young swine and measured ET and TNF-alpha. Septic swine developed systemic arterial hypotension and had significantly elevated TNF-alpha (4.15 +/- .41 U/ml at 1 h versus .40 +/- .13 U/ml at time zero) compared to control animals. ET levels were significantly elevated at 4 h (52.38 +/- 12.88 pg/ml vs. 10.45 +/- 1.82 pg/ml at time zero) and correlated negatively with the decline in cardiac output. We then passively immunized swine using anti TNF-alpha prior to the induction of sepsis to examine if TNF played a central role in the release ET. The anti TNF-alpha effectively removed circulating TNF-alpha bioactivity in septic animals. Anti-TNF-alpha-treated animals did not develop significant systemic arterial hypotension and had significant attenuation in endothelin (19.01 +/- 4.18 pg/ml at 4 h compared to 52.38 +/- 12.88 pg/ml in septic animals at 4 h) which correlated with preservation of cardiac output. TNF-alpha may cause cardiac dysfunction in sepsis syndrome through increased release of ET.

Fatal Cunninghamella bertholletiae infection in an immunocompetent patient.

The first fatal Cunninghamella bertholletiae infection in a clinically immunocompetent host is reported. This case differs from previously reported cases by the lack of extensive vascular invasion and thrombosis.

Measles pneumonia. Treatment of a near-fatal case with corticosteroids and vitamin A.

A 29-year-old woman experienced overwhelming rubeola pneumonia requiring endotracheal intubation and mechanical ventilation. Treatment with high-dose corticosteroids and vitamin A was accompanied by a prompt clinical response. Further investigation of this novel therapy is needed.

Anti-CD18 antibody attenuates neutropenia and alveolar capillary-membrane injury during gram-negative sepsis.

Activated polymorphonuclear leukocytes (PMNs) are implicated in the pathogenesis of acute lung injury (ALI) associated with sepsis. Adhesion of activated PMNs to endothelial monolayers is mediated by the CD18 adhesion-receptor complex on the PMN cell surface. Monoclonal antibody 60.3 (MoAb 60.3) blocks CD18-dependent PMN-endothelial adhesion in vitro and in vivo. This study was designed to determine the role of CD18-dependent PMN adhesion in ALI associated with gram-negative sepsis. Anesthetized, ventilated (FiO2 0.5, positive end-expiratory pressure 5 cm H2O) pigs received sterile saline (control, n = 8) or live Pseudomonas aeruginosa, 5 x 10(8) colony-forming units/ml at 0.3 ml/20 kg/min (septic, n = 9) for 1 hour. A third group (n = 7) received MoAb 60.3, 2 mg/kg intravenously, 15 minutes before Pseudomonas infusion. Animals were studied for 300 minutes. MoAb 60.3 significantly (p less than 0.05) attenuated the neutropenia seen in sepsis (15 +/- 1 vs 6 +/- 1 x 10(3) PMNs/mm3 at 300 min). Alveolar-capillary membrane injury was assessed by bronchoalveolar-lavage protein content and extravascular lung water determination. MoAb 60.3 significantly (p less than 0.05) reduced BAL protein at 300 minutes (388 +/- 75 vs 1059 +/- 216 micrograms/ml in septic animals) and attenuated the increase in extravascular lung water to 240 minutes (7.1 +/- 2 vs 14.2 +/- 1.2 ml/kg in septic animals). Systemic hypotension, decreased cardiac index, pulmonary hypertension, and relative hypoxemia, all characteristic of this model, were not altered by MoAb 60.3. These data suggest that, in this model of septic ALI, neutropenia is, in part, CD18 dependent and that blocking CD18-dependent PMN adhesion protects the alveolar-capillary membrane independently of altered hemodynamic status.

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.

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)

Assessment of exercise oxygen consumption as preoperative criterion for lung resection.

Determination of preoperative pulmonary function is crucial in avoiding complications from pulmonary resection. Many have employed static pulmonary function testing in an attempt to decrease morbidity and mortality from lung resections. The purpose of the present study was to correlate preoperative static pulmonary function, one-second forced expiratory volume (FEV1), and exercise O2 consumption (MVO2) with postoperative morbidity and mortality. Fifty consecutive patients underwent preoperative FEV1 and MVO2 determinations. A criterion for surgical resection included an FEV1 greater than 1.7 liters for pneumonectomy, greater than 1.2 liters for lobectomy, and greater than 0.9 liters for wedge resection. The surgeon was blinded as to the results of MVO2 studies. Mean age was 63.8 years (range, 47 to 76 years). There were 10 pneumonectomies, 28 lobectomies, and 12 wedge resections. Among the 50 surgical candidates selected solely on the standard FEV1 values, mortality was 4% (2/50) and morbidity, 12% (6/50). Stratification on the basis of exercise performance showed a 29% mortality (2/7) and a 43% morbidity (3/7) in patients with an MVO2 less than 10 ml/kg/min. Patients with an MVO2 less than 20 but greater than 10 ml/kg/min had a 10.7% morbidity (3/28), and there were no deaths. No patients with an MVO2 greater than 20 ml/kg/min sustained any morbidity or died (p less than 0.001). We conclude that exercise is an important criterion in the preoperative evaluation of patients for pulmonary surgery. An MVO2 less than 10 ml/kg/min is associated with significant morbidity and mortality.

Neuritic growth maintained near the lesion site long after spinal cord transection in the newborn rat.

The spinal cord of neonatal and weanling rats was mid-thoracically transected. Either 3 or 6 months later the borders of the lesion site were studied using electron microscopy. No sign of axonal regeneration through the lesion site was found in either group, even though the glial reaction was minimal in neonatal operates. In both groups of operates, reactive axonal endings, presumed to result from the original surgery, and neuritic growth were found in a reactive zone on both sides of the lesion site. We conclude that the potential for axonal growth (regeneration or generation) is maintained at the borders of the lesion in both groups of operates.

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.

Nonspecific cytotoxicity of recombinant interleukin-2 activated lymphocytes.

The administration of interleukin-2 (IL-2) and lymphokine activated killer (LAK) cells to patients with advanced metastatic cancer has yielded encouraging results. The purported ability of LAK cells to be discriminatively tumoricidal, thus sparing normal host tissue, represents a major advance over conventional chemotherapy. However, IL-2 adoptive immunotherapy results in dose-limiting toxicity characterized by weight gain, dyspnea, ascites, and peripheral-pulmonary edema suggestive of a vascular leak syndrome. It is unclear whether the observed toxicity is directly related to IL-2 and/or LAK cells. The authors examined the cytolytic nature of human LAK cells against human endothelial, epithelial, and fibroblast cell lines. Bovine endothelial cells also were studied. Using a 51Cr release assay, the cytolytic potential, time course, and effect of reactive oxygen intermediate inhibitors were studied. LAK cells were uniformly toxic against all cell lines, in contrast to high dose rIL-2 and excipient. Significant cytolysis was observed within 30 minutes and increased over the first 2 hours of LAK cells coming in contact with target cells. Reactive oxygen intermediate inhibitors did not reduce cytolytic activity. The authors thus found human LAK cells to be rapidly cytolytic against a variety of human and bovine cell lines. This cytolysis was independent of reactive oxygen intermediates.

[Evaluation of thromboprophylaxis in patients hospitalized in a tertiary care center: an applicable model of clinical practice evaluation. Revision of 320 cases]. / Évaluation de l'utilisation de la thromboprophylaxie chez les patients hospitalisés dans un centre hospitalier universitaire : un modèle applicable d'évaluation de la qualité de l'acte. Une revue de 320 patients hospitalisés.

OBJECTIVES: To analyze in-hospital thromboprophylaxis in patients at risk for venous thromboembolism. To evaluate compliance with heparin-induced thrombocytopenia screening recommendations in these patients. PATIENT AND METHODS: We performed a cross-sectional study of 395 patients hospitalized in our tertiary care center at risk for venous thromboembolism. We collected data regarding thromboprophylaxis (risk factors for thrombosis, type of prophylaxis, bleeding risk, demographic data, and hospitalization data). RESULTS: Three hundred and twenty patients were included in the study; 183 patients were hospitalized on medical wards and 137 patients on surgical wards. Thromboprophylaxis was indicated in 57% of the patients according to the American College of Chest Physicians' clinical practice guidelines. Adequate venous thrombosis prophylaxis was prescribed for 83.7% of these patients (76.1% of medical cases and 90.6% of the surgical cases). In contrast, only 47.1% of at risk patients on the family medicine wards received adequate prophylaxis. 79.3% of patients for whom it was indicated underwent appropriate platelet count monitoring. CONCLUSION: The use of thromboprophylaxis is well established in our institution. After having reviewed these data we instituted measures to improve our rate of appropriate thromboprophylaxis and platelet count monitoring. This type of evaluation could be considered by other centers in order to evaluate their performance and institute measures to improve their quality of care.