Disseminated tuberculosis in interferon gamma gene-disrupted mice.

The expression of protective immunity to Mycobacterium tuberculosis in mice is mediated by T lymphocytes that secrete cytokines. These molecules then mediate a variety of roles, including the activation of parasitized host macrophages, and the recruitment of other mononuclear phagocytes to the site of the infection in order to initiate granuloma formation. Among these cytokines, interferon gamma (IFN-gamma) is believed to play a key role is these events. In confirmation of this hypothesis, we show in this study that mice in which the IFN-gamma gene has been disrupted were unable to contain or control a normally sublethal dose of M. tuberculosis, delivered either intravenously or aerogenically. In such mice, a progressive and widespread tissue destruction and necrosis, associated with very high numbers of acid-fast bacilli, was observed. In contrast, despite the lack of protective immunity, some DTH-like reactivity could still be elicited. These data, therefore, indicate that although IFN-gamma may not be needed for DTH expression, it plays a pivotal and essential role in protective cellular immunity to tuberculosis infection.

Pharmacodynamics of prolonged oral etoposide in patients with advanced non-small-cell lung cancer.

PURPOSE: This study was undertaken to investigate the pharmacodynamic relationship between etoposide drug levels on 21-day oral treatment courses and hematologic toxicities in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty-two patients with stage IIIB or IV NSCLC were treated with oral etoposide 50 mg/m2/d for 21 consecutive days in combination with cisplatin 100 mg/m2 on day 1. Treatment was repeated every 28 days for up to six courses. Patients had not received previous chemotherapy and had a performance status of 0 to 2. Patients were monitored weekly while on treatment for compliance with oral etoposide and toxicity, including complete blood cell counts, and a blood sample before the daily etoposide dose (drug trough levels). Etoposide concentrations were measured in the plasma by high-performance liquid chromatography (HPLC). RESULTS: Three patients achieved a complete response (CR) and 10 patients a partial response for an objective response rate of 41% (95% confidence interval, 24% to 58%). The median survival was 4 months (range, 1 to 23). Neutropenia was dose-limiting, and two patients died of neutropenic sepsis. Pharmacodynamic correlations for drug concentrations and hematologic toxicities were available for 27 patients and a total of 76 treatment courses, and correlations were significant for graded hematologic toxicity and nadir counts of leukocytes, neutrophils, hemoglobin, and platelets. The grade of infection (77 courses) was also related to drug levels. Using data from 27 initial courses, a pharmacodynamic model was developed to estimate the nadir leukocyte or neutrophil count (WBCn, ANCn) based on the pretreatment count (WBCp, ANCp) and the etoposide concentration (Ec) as follows: WBCn = 0.35 (1 + WBCp x e-1.12 x Ec) and ANCn = 0.32 (1 + ANCp x e-2.47 x Ec). CONCLUSION: Etoposide concentrations are related to the resulting hematologic toxicities. It is possible to predict nadir counts in the first course by a pharmacodynamic model. The above equations need to be validated prospectively and may be useful in future studies of prolonged oral etoposide.

Bilateral diaphragmatic paralysis in association with neurogenic disease.

A patient had complete diaphragmatic paralysis and his disease progressed to include systemic neurological deficit. The cause is unknown. Appropriate diagnostic tests are emphasized, and a discussion of potential etiologies with a review of the literature of idiopathic diaphragmatic paralysis is presented.

Influence of morphine during pregnancy on neuroendocrine regulation of pituitary hormone secretion.

The effects of exposure to morphine during pregnancy on postnatal neuroendocrine systems were investigated. Rats received morphine sulphate or 0.9% (w/v) NaCl twice daily on days 5-12 of pregnancy. A dose of 5 mg morphine sulphate/kg was administered for the first three injections while 10 mg/kg was used for each of the remaining 13. This treatment regimen led to a significant delay in the onset of vaginal opening in the female offspring. Mothers treated with morphine sulphate showed a marked attenuation of their prolactin response to the suckling stimulus, although they still released significant amounts of the hormone. Both male and female offspring of the opiate-treated dams showed a major reduction in the sensitivity of their hypothalamic-pituitary axis to gonadal steroids at 15 days of age. No significant differences were found in the acute thyrotrophin response to single injection of morphine sulphate of prepuberal male and female pups of morphine- and saline-treated dams. These data show that exposure to opiates during critical periods of prenatal development lead to long-lasting alterations in the neuroendocrine control systems of the animal. These alterations may then have significant consequences on the physiological maturation and adult behaviour of the animal.

High-frequency jet ventilation. A prospective randomized evaluation.

Three hundred nine patients were randomly allocated to two ventilatory protocols; 157 patients were supported with a volume-cycled ventilator (VCV) (Bear Medical BEAR 1) and 152 with a high-frequency jet ventilatory (HFJV) developed at our institution. The two ventilators were compared for safety, reliability, ease of use, and efficacy in maintaining gas exchange. On VCV, end points of therapy were: fractional concentration of oxygen in the inspired gas (FIo2) less than or equal to 0.40; arterial oxygen pressure (PaO2) greater than or equal to 70 mm Hg; cardiac index (CI) greater than or equal to 3.5 L/min/sq m; and spontaneous respiratory rate less than or equal to eight breaths per minute. On HFJV, end points were: FIo2 less than or equal to 0.45; arterial oxygen saturation greater than or equal to 0.90; and CI greater than or equal to 3.5 L/min/sq m. Spontaneous ventilation and pulmonary venous admixture reduction were the goals on VCV, with oxygen transport the goal on HFJV, Total duration of use of the ventilators was approximately 800 days with both types of devices; there were no technical failures, and the incidence of barotrauma was less than 5 percent. The end point of mechanical ventilation was reached by a significantly higher percentage of the patients randomized to HFJV. Patients who failed to reach the therapeutic goal within 24 hours were crossed over to the other form of support. Those crossed from VCV to HFJV improved more rapidly and in greater number than those crossed from HFJV to VCV. When survival and total duration of stay in the intensive care unit were considered, there was no difference between VCV and HFJV. Considering data on gas exchange, VCV provided a higher PaO2 at equivalent positive end-respiratory pressure than HFJV. Alveolar ventilation was slightly better on HFJV. Differences were statistically but not clinically significant. On HFJV, oxygenation and ventilation were maintained with lower peak inspiratory pressures and smaller tidal volumes than those required for VCV. This investigation proves that HFJV is a safe and reliable method to provide mechanical support which does not, at this time, offer obvious benefits over VCV.

Prediction of postoperative pulmonary function with the lateral position test. A prospective study.

Ten patients undergoing pneumonectomy were evaluated with the lateral position test (LPT) in addition to routine pulmonary function tests (PFTs). On the basis of the percentage of ventilation estimated to be contributed by each lung on LPT, predictions were made for expected values for each patient's post-pneumonectomy PFTs. One to three months after surgery patients were again evaluated with complete pulmonary function studies. Results were found to agree closely with preoperative predictions in most patients. We conclude that the easily performed LPT, previously found to yield values which correlate with those found on bronchospirometry and macroaggregate lung scanning, does indeed yield acceptable results clinically and is deserving of more widespread application, especially in the large number of institutions without nuclear medicine capabilities.

Phase II study of prolonged oral etoposide in combination with intravenous cisplatin in advanced non-small cell lung cancer.

The objectives of the study were to evaluate the combination of cisplatin and prolonged oral etoposide for response rate, survival, and toxicity. The treatment regimen consisted of etoposide (50 mg/m2/day) p.o. for 21 consecutive days and cisplatin (100 mg/m2) i.v. on day 1 every 28 days for up to six courses. Patients with Stage IIIB or IV non-small cell lung cancer who had not received prior chemotherapy and had an ECOG performance status of 0-2 were eligible if they had normal bone marrow, liver and renal functions. Patients were followed weekly for toxicity including complete blood counts. The total number of patients entered in the study was 60, of whom 56 were male and four female, 40 white and 20 African Americans. Median age was 64 years (range, 39-77). Performance status 0, 1, and 2 was present in five, 39, and 16 patients, respectively. Fourteen patients had Stage IIIB and 46 Stage IV disease. A total of 142 treatment courses were administered (median 2, range 1-6). Three patients had a complete response and 19 patients had a partial response for an objective response rate of 37% (95% confidence interval, 31-43%). Median survival was 5 months (range, 1-39+). Neutropenia was the major toxicity with Grade 4 occurring in 25 patients after the first course. The following percent of patients experienced severe or life-threatening hematologic toxicity (Grade 3 and 4 combined) over all courses: leukopenia, 73%; neutropenia, 73%; anemia, 42%; and thrombocytopenia, 37%. Three patients died of neutropenic sepsis.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary capillary hemangiomatosis: a clinicopathologic review.

Pulmonary capillary hemangiomatosis is a locally aggressive benign vascular neoplasm of the lung characterized by the presence of numerous cytologically benign thin-walled capillary-sized blood vessels proliferating diffusely through the pulmonary interstitium, in and around pulmonary vessels and airways. Pulmonary capillary hemangiomatosis is a rare disease characterized by pulmonary hypertension and a slowly progressive clinical course; it is frequently misdiagnosed clinically as primary pulmonary hypertension and veno-occlusive disease. The purpose of this review is to describe the clinical, radiologic, and histologic features of this rare form of pulmonary vascular neoplasm, which may present considerable diagnostic problems to both the clinician and the histopathologist. Fourteen cases of pulmonary capillary hemangiomatosis have been previously reported. In this review we describe the fourth case of pulmonary capillary hemangiomatosis in which the diagnosis was made antemortem, as well as the fourth to undergo lung transplantation.

Preoperative assessment of the high-risk patient for lung resection.

BACKGROUND: We wanted to determine if cardiopulmonary exercise testing could better identify the threshold where physiologic function is irreparably impaired for patients with borderline pulmonary function who are being considered for lung cancer resection. METHODS: We performed an open, prospective preoperative trial and a postoperative outcome evaluation with a combined medical, surgical, and exercise physiology evaluation at three university hospitals. All eligible patients had spirometry, lung volume determination, and quantitative perfusion scanning and performed a cardiopulmonary stress test, stair climbing, and a 12-minute walk for distance. Functional status was determined with an Eastern Cooperative Oncology Group score, a dyspnea score, and a cardiopulmonary risk index. RESULTS: We identified 12 patients who met strict criteria for borderline pulmonary function during a 1-year study period. The mean forced expiratory volume in 1 second (FEV1) was 1.38 L (48% of predicted). The mean predicted postoperative FEV1 based on pneumonectomy was 700 mL. Eleven of the patients did the stair climb and 10 passed. All 12 patients achieved a maximum oxygen consumption greater than or equal to 10 mL x kg(-1) x min(-1) (mean value, 13.8 mL x kg(-1) x min(-1)). Thirteen operations were performed on the 12 patients. Nine complications occurred in 7 patients. CONCLUSIONS: Patients with borderline pulmonary function can undergo resection safely if they have an FEV1 equal to or greater than 1.6 L or 40% of its predicted value, a predicted postoperative FEV1 of 700 mL or more, a maximum oxygen consumption of 10 mL x kg(-1) x min(-1) or greater, or stair climbing of three flights or more. Cardiopulmonary stress testing and stair climbing add valuable clinical information for patients with an FEV1 of less than 1.6 L.

Increased pulmonary blood flow produces endothelial cell dysfunction in neonatal swine.

BACKGROUND: The mechanisms by which increased pulmonary blood flow results in pulmonary hypertension have not been determined. METHODS: To determine if increased pulmonary blood flow produces endothelial dysfunction that precedes vascular remodeling and smooth muscle proliferation, neonatal swine (n = 12) (age, 6.1+/-0.5 days) underwent ligation of the left pulmonary artery (LPA) to increase blood flow to the right lung. At 12 weeks of age, endothelium-dependent vasodilatation was assessed by acetylcholine infusion and endothelium-independent vasodilatation by inhaled nitric oxide (NO) in the LPA group and age-matched controls (CON) (n = 11). RESULTS: Mean pulmonary artery pressure was 24.1+/-3.0 mm Hg in the LPA group and 20.8+/-1.9 mm Hg in the CON group (p < 0.1). Pulmonary vascular resistance was 13.2+/-2.2 Wood units in the LPA group and 5.8+/-0.8 Wood units in the CON group (p = 0.001). Acute occlusion of the left pulmonary artery in the CON group increased pulmonary vascular resistance to 6.9+/-3.9 Wood units (p = 0.04). Administration of acetylcholine in the CON group after preconstriction with the thromboxane A2 analogue U46619 resulted in a 30.6%+/-5.4% decrease in pulmonary vascular resistance. In the LPA group, acetylcholine produced paradoxical vasoconstriction and a 15.4%+/-4.1% increase in pulmonary vascular resistance (p < 0.001 versus CON) indicating loss of endothelium-dependent vasodilatation. Nitric oxide decreased pulmonary vascular resistance by 41.9%+/-3.3% in the CON group and 30.8%+/-2.7% in the LPA group (p = 0.04 versus CON), indicating preserved endothelium-independent vasodilatation in both groups. Morphometric analysis was performed in 4 animals from each group. Medial wall thickness as percent of external diameter of small arteries (<100 microm) was the same in both groups (6.4%+/-0.4% in the LPA group versus 6.6% +/-0.4% in the CON animals; p > 0.1). CONCLUSIONS: Increased pulmonary blood flow in immature animals produces endothelial cell dysfunction with loss of endothelium-dependent vasodilatation before the onset of pulmonary vascular remodeling. Subsequent smooth muscle proliferation may be mediated by endothelium-derived factors.

Pharmacodynamics of three daily infusions of etoposide in patients with extensive-stage small-cell lung cancer.

The objectives of this study were to define the pharmacodynamics of etoposide and to develop potentially useful models (1) to estimate the plasma clearance using a limited number of samples and (2) to describe the relationship between clearance and the dose-limiting toxicity. A total of 17 patients with extensive-stage small-cell lung cancer were treated with 150 mg/m2 etoposide daily for 3 consecutive days and with 100 mg/m2 cisplatin on day 3 only. Both drugs were given intravenously over 1 h. Treatment was repeated every 21 days for up to six courses. All patients were newly diagnosed (no previous chemotherapy or irradiation) and had a performance status of 0-2. Six patients achieved a complete response as confirmed by repeat bronchoscopy and five patients showed a partial response, for an overall objective response rate of 65% (95% confidence interval, 38%-87%). The median survival was 8 months (range, 1-24+ months). The dose-limiting toxicity was neutropenia. Etoposide pharmacokinetics were measured during the first course and determinations were repeated during courses 3 or 4 and 6. Complete blood counts were obtained weekly. Correlations for etoposide clearance and hematologic toxicities were evaluated for 17 initial courses and for an overall number of 33 courses. Pharmacodynamic correlations were significant for graded hematologic toxicities, as well as nadirs of leukocytes, neutrophils, and platelets for the initial courses and for all courses. To reduce the requirement for numerous blood samples, a limited sampling model was developed to estimate the area under the concentration versus time curve (AUC) with the following equation: AUC = 15.45 + 3.86 x C2 + 7.10 x C4, where C2 and C4 represent the etoposide concentrations at 2 and 4 h, respectively. The total plasma clearance was calculated as the dose divided by the AUC; correlations with toxicity were better for clearance expressed in milliliters per minute than for that expressed in milliliters per minute per square meter of body surface area. The absolute neutrophil count at the nadir (ANCn) can be estimated by the following pharmacodynamic model, which is based on 33 courses: ANCn = -0.399 + 0.024 x Ecl, where Ecl represents the etoposide clearance expressed in milliliters per minute. Further studies are necessary to validate both models prospectively.

An historical survey of UK government measures to control the NHS medicines expenditure from 1948 to 1996.

Since the inception of the National Health Service in 1948, successive British governments have taken various measures to restrain the growth of the medicines bill. A total of 10 different measures have been introduced with very limited success. The most effective measures have been those directed at increasing the level of generic prescribing; such measures mean that the patient is treated with older, off-patent medicines which, although cheap, are not necessarily cost effective or the most clinically effective. Possible future directions for curtailing expenditure include controlling the price of off-patent branded medicines to the level of generic products, and the initiation of a government policy to actively encourage prescribing of newer medicines where these are shown to be more clinically effective or more cost effective.

The need for pharmacoeconomic evaluations in the NHS.

New medicines can be cost effective, and the under use of many therapeutic advances has been a cause for concern. Equally, the introduction of certain expensive products onto the market prematurely where adequate clinical studies have not been conducted equally represents an unsatisfactory situation. Many of these products that have reached the market 'too soon' have been for serious conditions where current treatments are inadequate and the new product represents a new hope which may or may not be realised. For some products, studies may have to take place after marketing and a condition for patients receiving treatment is that they are enrolled into a postmarketing study. Ultimately, decisions on the use of such treatments should be made after adequate clinical efficacy studies are available and independent pharmacoeconomic assessment has taken place. Decisions on the use of expensive treatments should be made nationally and not left to local health authorities desperate to balance their budgets.

5-Fluorouracil infusion and mitomycin combination chemotherapy in the management of patients with advanced non-small-cell lung cancer.

We have carried out a phase II study evaluating the activity of a 5-fluorouracil drug combination in patients with advanced non-small-cell lung cancer. Patients were given 60 mg/m2 of methotrexate i.v. on day 1. On day 2, 750 mg/m2 of 5-fluorouracil was administered as a 24-h infusion daily for 3 days. Also on day 3, 10 mg/m2 of mitomycin was given i.v. along with folinic acid. Folinic acid was started on day 3 initially at a dose of 25 mg/m2 intravenously every 6 h for three doses, followed by a 2-h infusion of 200 mg/m2 daily on days 3 and 4. Therapy was repeated every 28 days. Fourteen of 35 patients (40%) experienced a partial response to chemotherapy. The median survival of the entire group was 19 weeks. Mucositis was a common side effect but severe leukopenia, anemia, renal insufficiency, and skin ulceration were rare. This study demonstrated that 5-fluorouracil infusion therapy has activity in advanced non-small-cell lung cancer but the responses are not durable. Further studies evaluating differing dose schedules and alternate 5-fluorouracil infusion-based drug combinations seems warranted.

Calculation of sodium bicarbonate requirement in metabolic acidosis.

Despite the host of complications which may be associated with intravenous sodium bicarbonate infusion, the use of this agent is a frequent necessity in patients with metabolic acidosis. No satisfactory formula for calculating bicarbonate dose had previously been described, although such an approach might be expected to reduce the incidence of these complications. The authors have devised a simple formula for bedside calculation of bicarbonate requirement in metabolic acidosis, designed to elevate th pH to the region about 7.30, and report their experience with the use of this formula in 13 instances. In all but one, the post-infusion pH was between 7.25 and 7.37, with a mean of 7.30 +/- 0.04 and no instances of serious overtitration. It is concluded that the formula is useful as a pragmatic aid in the management of patients with metabolic acidosis.

Case report: acute postoperative respiratory failure caused by Chlamydia pneumoniae and diagnosed by bronchoalveolar lavage.

Most Chlamydia pneumoniae infections are mild, but 10% develop into pneumonia. C. pneumoniae has been observed in hospital in intubated patients undergoing major surgery or admitted with severe trauma. A patient with squamous cell carcinoma in whom severe pneumonia developed postpneumonectomy and who required mechanical ventilation is presented. The patient was initially treated for nosocomial bacterial pneumonia with the broad spectrum antibiotics ceftazidime, amikacin, and vancomycin. The patient underwent a bronchoalveolar lavage, from which C. pneumoniae was grown. Generally, these patients are a high-risk mortality group. Only after substituting the above antibiotics with doxycycline, to which C. pneumoniae was sensitive, did the pneumonia respond. Whether this was a nosocomial or a community-acquired pneumonia is uncertain.

Immunolocalization of stress proteins and extracellular matrix proteins in the rat tibia.

Stress proteins (heat shock proteins [hsps]) serve a number of protective functions, including protection from apoptosis and acting as chaperones during protein biosynthesis. For example, hsp 27 has been defined as a chaperone for the G3 domain of aggrecan, while hsp 47 is the chaperone for type I collagen. Separate cytoprotective roles for hsp 27 and hsp 70 have been demonstrated. The aim of this study was to define the expression of hsps in osteoblastic and chondrocytic cells of the growing rat long bone in relationship to the immunohistochemical localization of aggrecan, type I collagen and the presence of fragmented DNA that defines apoptotic events. Tibiae were harvested from Fisher 344 rats (n=6) and fixed in 10% buffered formalin. Samples were decalcified in 10% EDTA, bisected, and processed for histologic examination. Sections (5 mm) were immunohistochemically stained using a streptavidin-biotin detection method. Co-localization of hsps with apoptosis was achieved using the TUNEL procedure. In the rat tibia growth plate, aggrecan was generally distributed throughout cartilage and chondrocytes. However, hsp 27 expression was observed only in the lower hypertrophic chondrocytes. hsp27 was present in osteoblasts lining newly formed bone. hsp 47 staining was also prominent within these osteoblasts where collagen type I immunolocalization occurred. The inducible form of hsp 70 was localized to the osteoblastic cells lining new bone in the primary spongiosa. In cartilage, DNA fragmentation was restricted to the hypertrophic, hsp27-positive, chondrocytes. In contrast, DNA fragmentation was not co-localized with hsp27-positive osteoblastic cells of the primary spongiosa, although occasional apoptotic cells were identified. These results indicate that apoptosis is a mechanism by which hypertrophic chondrocytes are eliminated from cartilage prior to calcification, but that other mechanisms are also likely to be involved. They also suggest that hsps have cytoprotective and biosynthetic functions within osteoblasts and chondrocytes, but apoptotic signals may override these effects in some instances, resulting in apoptosis.

Nursing care of the immunosuppressed patient in an intensive care unit.

In summary, a comprehensive investigation into the etiologies of immunosuppression within a critical care unit has been described. Nursing interventions appropriate for these patients have been detailed.

Role of the oncology nurse when the patient with cancer is transferred to the critical care unit.

Patients with cancer can become critically ill from treatment-related complications or from progressive disease. The oncology nurse can positively influence the care of the patient and family during and after transfer to the Intensive Care Unit (ICU) by maintaining a strong advocacy role. Patient and family education can prevent or alleviate many of the psychological discomforts precipitated by critical illness. Open communication between the oncology and critical care staff can ease discussion about ethical issues.

The effects of progressive muscular relaxation on subjectively reported disturbance due to hospital noise.

Hospital noise has repeatedly been demonstrated to exceed levels recommended by the Environmental Protection Agency. Hospital noise from staff and machinery has been implicated in the etiologies of many behavioral disorders such as sleep deprivation, sensory overload, and altered comfort levels. Relaxation techniques have been shown to be effective in decreasing the aversiveness of many situations. This study tested the effects of progressive muscular relaxation (PMR) on subjectively reported disturbance due to hospital noise. In addition, noise sensitivity as a personality attribute was correlated with disturbance due to hospital noise and efficacy of PMR. A sample of 100 acutely ill hospitalized patients were randomly assigned to an experimental group or control group. The experimental group was instructed in the Bernstein-Borkovec technique of PMR; the control group received a short visit. Results revealed that the experimental groups had a significantly lower amount of disturbance due to hospital noise after being instructed in the use of PMR than prior to the intervention. Control group subjects demonstrated no such change. Noise sensitivity was found to be unrelated to either disturbance due to hospital noise or efficacy of PMR in decreasing disturbance due to hospital noise.